pegs final agenda pegs - pegs summit europe · of protein therapeutics, together with case studies...

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RECORD ATTENDANCE CONFIRMED FOR 2015!

Final Weeks to Registerfor the Largest

PEGS Europe Ever!

• Network with 700 colleagues from 30+ countries

• See unpublished data from industry leaders

• Learn from 175 speakers and 125 poster presenters

• Record attendance each of the last three years

PLENARY KEYNOTESLorenz Mayr, Ph.D., AstraZeneca

Paul W.H.I. Parren, Ph.D., Genmab B.V.

Andreas Plückthun, Ph.D., University of Zurich

Tristan J. Vaughan, Ph.D., MedImmune Ltd.

Gregory A. Weiss, Ph.D., University of California, Irvine

PEGSProtein & Antibody Engineering Summit

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Final Weeks to Register for the Largest PEGS Europe Ever!PEGSummitEurope.com

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CONFERENCE-AT-A-GLANCE

SPONSORS

SHORT COURSES

Antibody Engineering StreamDisplay of Antibodies

Bispecifics and Novel Biotherapeutics

Cancer Biotherapeutics

Biologics Development StreamOptimisation & Development

Aggregates & Particles

Characterising Biotherapeutics

Impurities & Stability StreamPurification Technologies


Formulation & Stability

Bioproduction StreamPurification Technologies

Bioreactor Design & Engineering

Scaling-Up & Down

Protein Expression StreamEngineering Expression Systems

Applying Expression Platforms

Scaling-Up & Down

SPONSOR & EXHIBIT OPPORTUNITIES

HOTEL & TRAVEL INFORMATION

REGISTRATION INFORMATION

FINAL AGENDA

2-6 NOVEMBER 2015 | EPIC SANA LISBOA HOTEL | LISBON, PORTUGAL


Seventh Annual

https://chidb.com/reg/pge/reg.asp

CORPORATE SUPPORT SPONSORS

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CONFERENCE-AT-A-GLANCEAntibody

Engineering StreamBiologics

Development StreamImpurities &

Stability StreamBioproduction

StreamProtein Expression

Stream

2 November:Monday morning Pre-Conference Short Courses*

2-3 November: Monday afternoon - Tuesday

Display of Antibodies Optimisation & Development

Purification Technologies

Purification Technologies

Engineering Expression Systems

4-5 November: Wednesday - Thursday morning

Bispecifics & Novel Products





5 November:Thursday evening Dinner Short Courses*

5-6 November: Thursday afternoon - Friday




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“I was pleased to find so many scientists in the European industrial sector who were willing to talk about their research in great detail. It is a refreshing viewpoint when compared to similar conferences held in the US.”

Kathleen H., Ph.D., Scientist, Cell and Systems Biology, University of Toronto

“The best biologics technology meeting in Europe.” Rakesh D., Ph.D., VP, R&D, MedImmune

“The presentations were exceptional, covering an extraordinary array of antibody and antibody-alternative technologies. PEGS Europe is unparalleled in both scope and quality.”Kevin R., Ph.D., Scientist, Wellcome Trust Sanger Institute

“A great overview highlighting almost all aspects of antibody development of the current and next generation. Almost a perfect conference.”Peter S., Ph.D., CSO, SuppreMol

*Separate registration required

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MORNING SHORT COURSES

MONDAY, 2 NOVEMBER, 9:00 – 12:30

SC1: Engineering of Bispecific AntibodiesNicolas Fischer, Ph.D., Head, Research, Novimmune SAMichela Silacci, Director, Discovery Research, Covagen AG, one of the Janssen Pharmaceutical Companies of J&JBy attending this interactive workshop, you will learn about the various approaches used for the engineering of bispecific antibodies and bispecific scaffold-based binding proteins. Different technologies will be compared, and examples for applications of bispecific antibodies in drug development will be presented with a focus on candidates that are currently being evaluated in clinical trials. Opportunities and challenges in the field of bispecific antibodies will be discussed.

SC2: Mutation and Selection Strategies for Multi-Parameter Antibody OptimisationWilliam Finlay, Ph.D., Senior Director, Global Biotherapeutic Technologies, Pfizer, Inc.Orla Cunningham, Ph.D., Associate Director, Global Biotherapeutic Technologies, Pfizer, Inc.In therapeutic antibody discovery, few lead molecules meet all of the demanding standards required to become a drug. As a result, most antibodies will require some form of engineering and optimisation. This course aims to help attendees navigate the complex workflows and technological options required to be successful.

SC3: CHO Cell EngineeringAnton Bauer, Ph.D., COO, The Antibody LabSimon Fischer, Ph.D., Scientist, BP Process Development Germany, Boehringer Ingelheim Pharma GmbH & Co. KGZhiwei Song, Ph.D., Principal Scientist, Lead PI for GlycoSing Programme, Bioprocessing Technology Institute, A*STARRecombinant protein therapeutics have proven their worth as invaluable pharmaceuticals. Chinese hamster ovary (CHO) cells are the primary choice by industry for the production of these proteins, owing to their capacity for correct folding, assembly and posttranslational modification. The growing demand for therapeutic proteins necessitates the development of new technologies for high quality and productivity in CHO expression systems. This course explores CHO cell engineering strategies to improve and select for the highest producers.

SC4: Protein Purification Strategies: Dealing with Proteins that Are Prone to AggregateMario Lebendiker, Ph.D., Head, Protein Purification Facility, Wolfson Centre for Applied Structural Biology, The Hebrew University of JerusalemThis course will provide a comprehensive and detailed outline of hands-on issues for purifying proteins. We will first address general considerations about the protein we want to produce, including issues of activity, solubility, homogeneity, purity, and proper oligomeric conformation. Aggregation is one of the main obstacles in protein production, so we will look at how to monitor for aggregation and comprehend its mechanism. We will also discuss how to check for the optimal solubility conditions at the expression level, and our comprehensive approach for optimizing solubility during purification. We will also discuss expression screening methodology, environmental factors to consider during purification, families of additives, and screening for additives. Lastly, we will address ways to avoid aggregation, as well as setting up protein concentration and storage.

SHORT COURSES* Make the Most of Your Time in Lisbon! Maximize your educational and networking opportunities by adding a short course.

*Separate registration required for short courses


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SHORT COURSES* Make the Most of Your Time in Lisbon! Maximize your educational and networking opportunities by adding a short course.

DINNER SHORT COURSES

THURSDAY, 5 NOVEMBER, 17:30 – 20:30

SC6: Troubleshooting and Engineering of Antibody ConstructsJonas Schaefer, Ph.D., Head, High-Throughput Binder Selection Facility, Biochemistry, University of ZurichJulia Neugebauer, Ph.D., Associate Director, Leader Discovery Programs, MorphoSys AGRecombinant antibodies vary widely in their biophysical characteristics, from stable monomers to metastable aggregation-prone oligomers. In particular, antibody variable domains differ in their intrinsic thermodynamic stability and may require labour-intensive engineering. It is therefore essential to implement antibody engineering strategies in screening and initial characterisation project phases in order to avoid time and cost consuming optimisation strategies in later development. In addition, it is critical to understand how the poor stability of individual variable domains not only limits the biophysical properties of small fragments, but also affects the production yield, stability and homogeneity of full-length IgGs containing these domains.

SC7: Immunotherapy in the 21st Century: More Specificity, More Potency, Better TargetingChristian Klein, Ph.D., Head, Oncology Programs, Roche Pharmaceutical Research & Early Development, Roche Innovation Center ZurichJos Melenhorst, Ph.D., Director, Product Development & Correlative Sciences Labs, University of PennsylvaniaPart One of this course will give an overview of validated and emerging targets for cancer immunotherapy and mechanisms of action of antibody-based cancer immunotherapy. It will cover ADCC-enhanced antibodies, T cell bispecific antibodies, CAR-T; and checkpoint inhibitory and agonistic antibodies. Part Two will discuss current cellular therapies of cancer, and how the synergy of basic biology, translational research, and biotechnology have allowed us to better target tumour cells, enhance the potency, and look for new ways to collaborate across the immune system.

SC8: The Challenge of Protein Aggregation and Formation of Sub Visible Particles in the Development of BiopharmaceuticalsTudor Arvinte, Ph.D., Chairman & CEO, Therapeomic, Inc.Attendees of this 3-hour short course will gain a critical overview of the complexity and diversity of the aggregation and sub-visible particles of peptide and protein biopharmaceuticals and on strategies to overcome these issues. The course will cover different aggregation mechanisms; available techniques for detection of aggregation and impurities and how these methods can be applied; strategies for developing stable peptide drug formulations using HT analysis and HT formulation platforms; as well as aggregation of biopharmaceuticals in human plasma – a new development and research field.

SC9: Advanced Techniques for Characterisation of Protein Aggregates, Particulates and ContaminantsMatthew Brown, Ph.D., Life Science Specialist, Malvern InstrumentsAmber Fradkin, Ph.D., Associate Director, R&D, KBI BiopharmaStacy Kenyon, Ph.D., Scientist, Bioscience Development Initiative, Malvern InstrumentsUnderstanding the complex process of protein aggregation is key to the implementation of QbD approaches during biotherapeutic development or deviation resolution of legacy products. Such in-depth understanding relies on the implementation of advanced characterization technologies. Using these advanced techniques, the biopharmaceutical industry is now offered detailed insights into protein behaviour, allowing evaluation of product stability and process impact. This course will cover some of the latest technologies for advanced characterization of protein therapeutics, together with case studies from industry, on how such approaches can be implemented for product development and understanding.

*Separate registration required for short courses


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ANTIBODY ENGINEERING STREAM

2-3 November 2015 | SECOND ANNUAL

Display of AntibodiesEmpowering Novel Biologics

Recommended Short Course*SC1: Engineering of Bispecific Antibodies(*Separate registration required. Please see Page 3 for more details.)

MONDAY, 2 NOVEMBER

12:00 Conference Registration

COMBINED KEYNOTE SESSION

13:40 PEGS Europe Team Welcome

13:45 Chairperson’s Opening RemarksDarrell Sleep, Director, Novozymes Biopharma R&D

13:50 Protein Engineering for New Modes of Actions and New Targets

Andreas G. Plückthun, Ph.D., Professor & Director, Biochemistry, University of ZurichUsing different display technologies and structure-based engineering, the possibilities of hitting extra- and intracellular targets will be

discussed, with an emphasis on extending the modes of action previously possible. The lecture will emphasise the need for interdisciplinary approaches.

14:30 Targeting Ion ChannelsTristan J. Vaughan, Ph.D., Senior Director, Antibody Discovery & Protein Engineering, MedImmune Ltd.Ion channels are complex integral membrane proteins that form a pore through which ions selectively pass down an electrochemical

gradient. They are prominent components of the nervous system where they can mediate transduction across synapses. Hence, certain channels represent good drug targets, especially for alleviating pain. Approaches will be described to target such ion channels with antibody-based drugs and a case study presented.

15:10 Current and Future Trends in Antibody TherapeuticsPaul W.H.I. Parren, Ph.D., Senior Vice President & Scientific Director, Preclinical Development & Research, GenmabTargeted treatment using antibody therapeutics has proved successful in the development of meaningful treatments in diverse

therapeutic areas. However, despite strong advances, many patients still fail to respond or become resistant to targeted treatment and novel innovative approaches to improve therapy are therefore required. Genetic and chemical engineering of antibodies, fueled by recent molecular insights, is providing important opportunities for the development of more potent antibody therapeutics. Examples from Genmab’s portfolio will be provided.

15:50 Refreshment Break in the Exhibit Hall with Poster Viewing

EUKARYOTIC DISPLAY

16:30 Chairperson’s RemarksJohn McCafferty, Ph.D., Co-Founder, Director and CEO, IONTAS Ltd.

16:35 Yeast-Based Platform to Select Rare Specificities and High Affinity AntibodiesTrevor A. Wattam, Ph.D., Manager, Biopharm Discovery Group, GlaxoSmithKlineThis talk will provide an overview of GSK experiences with Adimab’s yeast-based platform. It will provide an overview of the lead discovery processes. In addition a couple of case studies will be presented demonstrating the power of employing FACS-based selection to identify rare specificities and select high affinity antibodies.

17:05 Construction and Use of Large Antibody Libraries in Mammalian CellsJohn McCafferty, Ph.D., Co-Founder, Director and CEO, IONTAS Ltd.Using nuclease-directed integration of antibody genes we have constructed large libraries in mammalian cells containing a single antibody gene/cell. This allows surface display of antibodies, including IgG formatted antibodies, on the cell surface. This will permit the screening of millions of clones by flow sorting and provide information on both expression level and the extent of binding within the cell types used for antibody production.

17:35 Antibody Library Display on a Mammalian Sponsored by Virus: Combining the Advantages of Panning and Cell Sorting in One TechnologyErnest S. Smith, Ph.D., Senior Vice President, Research & Chief Scientific Officer, Vaccinex, Inc.We have developed an antibody discovery platform that enables efficient mammalian cell based expression of a library of human antibodies in full length IgG format on the surface of a mammalian virus. Upon infection of mammalian cells the antibody is not only incorporated into newly produced virus, it is also displayed on the surface of the host cell. This technology allows us to combine the advantages of virus panning and cell sorting into one technology.

18:05 Welcome Reception in the Exhibit Hall with Poster Viewing

19:05 End of Day One

TUESDAY, 3 NOVEMBER

07:45 Registration and Morning Coffee

NEW TECHNOLOGIES

08:30 Chairperson’s RemarksKerry Chester, Ph.D., Professor, Molecular Medicine, University College London Cancer Institute


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08:40 DNA-Encoded Chemical Libraries for the Isolation of High-Affinity Binding Ligands: An Alternative to AntibodiesDario Neri, Ph.D., Professor, Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zürich)The tagging of chemical compounds with DNA fragments, serving as amplifiable identification barcodes, allows the construction and screening of libraries of unprecedented size. The isolation of small organic ligands from DNA-encoded chemical libraries facilitates drug discovery applications.

09:10 Deep Microfluidic Screening for Discovery of Rare Antibodies with Optimal PropertiesWilliam S. Somers, Ph.D., Vice President, Global Biotherapeutic Technologies, PfizerWe are in a collaboration with HiFi Bio to establish a next generation microfluidic platform for antibody discovery that is allowing us to screen very large numbers of B-cells from humans and immunized animals for molecules that possess properties of interest. The massive throughput of the instrument and information rich assays allow us to identify rare antibodies that have both the biological activity of interest and favorable manufacturing properties.

09:40 PROBLEM SOLVING ROUNDTABLE DISCUSSIONS

Table 1: The Role of in vivo Molecular Imaging in the Development of ImmunotherapyModerator: Adam Badar, Ph.D., Head, Preclinical Nuclear Medicine, Centre for Advanced Biomedical Imaging (CABI), University College London

Table 2: Comparison of Technologies: Hybridoma, Phage, Transgenics and the Kitchen SinkModerator: Jacob Glanville, CSO, Distributed Bio LLC

Table 3: Next-Generation Sequencing of Phage Display Panning Output Pools to Guide Antibody Lead SelectionModerator: Stefan Ewert, Ph.D., Senior Investigator, NIBR Biologics Center, Novartis Pharma AG

10:40 Coffee Break in the Exhibit Hall with Poster Viewing

USING DISPLAY FOR IMMUNOTHERAPY APPLICATIONS11:15 Chairperson’s RemarksKerry Chester, Ph.D., Professor, Molecular Medicine, University College LondonCancer Institute

11:20 Engineered T Cell Receptors as Tools for the Study of Peptide–MHC InteractionsGeir Åge Løset, Ph.D., Researcher, Centre for Immune Regulation and Department of Biosciences, University of Oslo; CSO, Nextera ASThe use of phage display as tool to evolve cloned T cell receptors represents an attractive avenue to generate reagents for mechanistic studies of native pMHC engagement. We have systematically looked into domain format variants and phage

display engineering to obtain such functional soluble T cell receptors allowing for a deeper disease mechanism elucidation within autoimmunity. In parallel, we have also developed alternative pMHC-targeting units by phage display.

11:50 Multiscale, Multimodal in vivo Imaging of CAR T Cell TherapiesAdam Badar, Ph.D., Head, Preclinical Nuclear Medicine, Centre for Advanced Biomedical Imaging (CABI), University College LondonAdoptive immunotherapy using chimeric antigen receptor (CAR) engineered T cells has shown promising results in treating various cancer types. In vivo imaging plays a key role in the development of CAR T cell therapies, allowing us to study their homing, engraftment, expansion, persistence and demise longitudinally and non-invasively in animal and man. This talk will provide an overview of current state-of-the-art multiscale and multimodality imaging technologies available.

12:20 Screening and Charactersation of Biologics Sponsored by using a High Sensitivity Plate-based Laser Scanning CytometerPaul Wylie, Ph.D., Head, Instrumentation Applications Group, TTP LabTech LimitedThe mirrorball fluorescence cytometer is applicable to many stages within biologics discovery from screening to identify hits to binding characterisation and monitoring phenotypic responses. Streamlined no wash cell or bead-based assays provide process efficiencies over standard Flow or ELISA formats, enabling you to do more with precious samples and time.

12:35 Efficient Mammalian Cell Transfection for Sponsored by Antibody DiscoveryMichael Dyson, CTO, IONTAS LtdTransfection of mammalian cells is important for therapeutic antibody discovery including antigen production and antibody expression for functional screening. A comparison of different transfection methods in CHO and HEK293 cells will be presented. Transfection of mammalian cells has also been used to create libraries of antibodies displayed on the surface of mammalian cells and for the display of engineered T cell receptors.

12:50 Deep Sequencing of Paired VH-VL Regions from Sponsored by in Vitro Selection AssaysChris Mozdzierz, Ph.D., Associate Manager, Next-Generation Sequencing, GENEWIZIn this presentation, GENEWIZ’s Chris Mozdzierz will discuss Deep Sequencing of Paired VH-VL Regions from in vitro Selection Assays. He will also discuss how innovative technologies such as GENEWIZ’s FuzeSeq Antibody Sequencing can help overcome the existing limitations of conventional NGS.

13:20 Session Break

14:00 Dessert Break in the Exhibit Hall with Poster Viewing


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ANTIBODY GENERATION

14:30 Chairperson’s RemarksGregory A. Weiss, Ph.D., Professor of Chemistry, Molecular Biology and Biochemistry, University of California, Irvine

14:35 Next-Generation Sequencing of Phage Display Panning Output Pools to Guide Antibody Lead SelectionStefan Ewert, Ph.D., Senior Investigator, NIBR Biologics Center, Novartis Pharma AGWith the availability of bench-top personal sequencers it is now possible to apply Next Generation Sequencing (NGS) of Phage Display panning output pools during the antibody discovery process. Starting with a polyclonal 1.0E+06 Phage Display output pool after 3 panning cycles followed by adapted panning conditions and NGS analysis, we have been able to predict cross-reactivity profiles and biophysical properties like melting temperature of antibody candidates. Ultimately, we aim to replace classical screening methods and rely solely on adapted panning strategies followed by NGS to identify antibody leads out of the complete Phage Display output pool.

15:05 Call of the Wild: A New Generation of Antibody Discovery from Natural SourcesJacob Glanville, CSO, Distributed Bio LLCThe integration of new immunological insights, phage indexing technologies, and seven years NGS algorithm development has armed new design principles to harvest antibodies from natural repertoires. First, we review modeled insights gained from attempting to mimic nature by synthetic methods, with applications in in vitro SHM replacement and novel humanization technology. Next, we present a computationally-guided SuperHuman library built from natural sources. Finally, we describe a Survivor library generated from the blood of an army of cancer survivors.

15:35 Phenotypic Screening for Novel Antibody Targets in the Tumour MicroenvironmentRalph R. Minter, Ph.D., Fellow, Antibody Discovery and Protein Engineering, MedImmune Ltd.There is growing interest in finding and validating novel targets in the tumour microenvironment, especially in the burgeoning field of immunotherapy. We have been using phage display and phenotypic screening of antibodies to identify and validate novel targets both on cancer cells and immune cells which infiltrate tumours. Examples will be given to demonstrate the advantages of phenotypic screening for the identification of targets and drug leads in this context.

16:05 Combining the Benefits of Immunized Libraries, Sponsored by in vitro Selections and Computational Design for Antibody DiscoveryVera Molkenthin, Ph.D., Chief Scientist, AbCheck s.r.oRabbits are known to produce high affinity and diverse antibodies even against difficult targets. A library-based method allows the humanization of the complete VH/VL sequence repertoire of an immunized rabbit in one batch and offers a new approach to antibody discovery. The libraries are computationally designed for optimal developability properties, excluding T-cell epitopes and biochemical liabilities. Special strategies allow the selection of antibodies with slow dissociation rates, species cross reactivity and high thermal stabilities.


TARGETING DIFFICULT ANTIGENS WITH DISPLAY TECHNOLOGIES

17:10 Chairperson’s RemarksClaire Dobson, Ph.D., Associate Director, Antibody Discovery & Protein Engineering, MedImmune Ltd.

17:15 Dissecting and Engineering Phage-Displayed Membrane ProteinsGregory A. Weiss, Ph.D., Professor of Chemistry, Molecular Biology and Biochemistry, University of California, IrvineMembrane proteins (MPs) control the cell’s communications, sensing and responses to extracellular events. Yet MPs most remain off-limits to conventional protein engineering. The Weiss laboratory has reported a new type of bacteriophage allowing display and mutagenesis of this important class of proteins. The approach opens new frontiers to dissect and tailor binding by MPs and their binding partners. Several examples illustrating the power of the approach will be presented.

17:45 Computer-Guided Design of Antibodies Combined with Display Technologies to Identify Antibodies to Difficult TargetsYanay Ofran, Ph.D., Founder, Biolojic Design Ltd.Display technologies select for binding, not for activity. But the functional effect of an antibody is determined by the mode of binding, not only by the affinity. This talk will present a data-driven computational approach for designing of libraries that can yield binders with a preselected mode of binding. It has shown success in designing antibodies against difficult targets as well as bi-specific antibodies.

18:15 Targeted Modulation of hERG Channel Activity with scFv Antibody FragmentsCarol A. Harley, Ph.D., Research Scientist, Structural Biochemistry, IBMC- Instituto de Biologia Molecular e CelularThe KCNH voltage-dependent potassium channels have key roles in diseases such as cardiac LQT2 syndrome, schizophrenia and cancer. The intracellular domains of the hERG ion channel are important for modulating it´s activation properties. We have isolated and identified novel scFv antibodies that target specific regions within the N-terminal cytoplasmic domain of the hERG channel which modulate channel kinetics. This opens up a novel mode of ion channel modulation.

18:45 End of Display of Antibodies


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4-5 November 2015 | SEVENTH ANNUAL

Bispecifics and Novel BiotherapeuticsPlatform Development, Structure/Function Relationship, and Target and Target Pair Selection

Recommended Short Courses*SC1: Engineering of Bispecific AntibodiesSC2: Mutation and Selection Strategies for Multi-Parameter Antibody OptimisationSC6: Troubleshooting and Engineering of Antibody Constructs(*Separate registration required. Please see page 3 for more details.)

WEDNESDAY, 4 NOVEMBER


BISPECIFIC PLATFORMS

08:30 Chairperson’s Opening RemarksJonas V. Schaefer, Ph.D., Head, High-Throughput Binder Selection Facility, Biochemistry, University of Zurich

»KEYNOTE PRESENTATION08:35 Re-Envisioning “Classical” Cancer Therapy through the Lens of the Immune System to Develop Optimal Combination Immune Therapies

Israel Lowy, M.D., Ph.D., Vice-President, Clinical Sciences; Head, Translational Science and Oncology, Regeneron Pharmaceuticals, Inc.Regeneron is conducting new clinical trials with REGN1979, an anti-CD20xCD3 bispecific antibody, to treat CD20+ NHL or CLL, and

REGN2810, an anti-PD-1 mAb for multiple tumor types. Each is being developed as an immunologic foundation for therapeutic regimens capable of eliciting durable responses. Further augmentation of anti-tumor activity by combination with classical agents will not rely on standard of care dosing, but instead seek to optimize their immune enhancing effects.

09:20 Seamless Bispecific Antibody Discovery and Development Using the Duobody Platform: An EGFR x cMet Case StudyJanine Schuurman, Ph.D., Vice President, Research, Genmab B.V.The DuoBody platform represents a novel and elegant post-production technology for the generation of stable bispecific antibodies. General strategies, and considerations, for bispecific antibody discovery will be discussed. The suitability of the DuoBody platform for bispecific discovery approaches, showing the importance of doing this in the final format - illustrated by surprising findings, will be shown in a case study selecting a lead cMetxEGFR bispecific antibody.

09:50 Generation, Novel Insights and Clinical Update of Factor VIII Mimetic Bispecific Anti-Factor IXa/Factor X IgG AntibodyTomoyuki Igawa, Ph.D., Group Manager, Discovery Research, Chugai PharmaceuticalACE910 is a humanised anti-factors IXa and X bispecific IgG that places two factors into proximity and mimics factor VIII function for treating hemophilia A overcoming the issues of current treatment. Generation of ACE910, novel insights in unique contribution of non-antigen contacting region on the activity, and interim data of the Phase I and extension study combined will be presented.

10:20 Engineering Next-Generation Biotherapeutics: Developability & ManufacturabilityMaria Wendt, Ph.D., Head, Science, Biologics, GenedataNext-generation biotherapeutics, specifically bi- and multi-specifics, alternative scaffolds, and ADCs, provide significant advantages over traditional IgG-based molecules. However, as highly engineered molecules they pose new design, cloning, expression, purification, and analytics challenges. Our workflow platform automates the engineering, production, and testing of large panels of these candidate therapeutic molecules. We demonstrate the platform’s capability to explore the huge combinatorial space of novel molecule-specific designs, its high-throughput capability, and its built-in tools for developability and manufacturability assessments.


11:30 Development of Dual-Targeting Anti-CD47 Bispecific AntibodiesKrzysztof Masternak, Ph.D., Head, Biology, Research, Novimmune SADual-targeting antibodies (kλ-bodies) allow selective CD47 neutralisation in cancer cells expressing a particular cell surface antigen (in this case, CD19 or mesothelin), which is important, given that CD47 is ubiquitously expressed – including in RBC, platelets and other blood cells. I will present recent in vivo and in vitro data showing that our dual-targeting anti-CD47 bispecific antibodies have superior pharmacological properties in the clinic (PK, toxicity, a broad therapeutic window) as compared to monoclonal anti-CD47 antibodies.

12:00 Novel Bispecific Antibodies for Treatment of Chronic Hepatitis B Virus Infection and Associated TumoursFelix Bohne, Ph.D., Principal Investigator, Institute of Virology, Helmholtz Centre MunichChronic hepatitis B is characterised by exhausted effector cells incapable of eradicating the virus. To circumvent this limitation, HBV-specific retargeting of immune effector cells using bispecific monoclonal antibody (BiMab) constructs is a promising therapeutic approach. ScFv-driven tetravalent BiMab showed excellent PBMC-retargeting efficacy and in vitro killing of HBV-transgenic and infected hepatocytes. Translation into a relevant humanised mouse model yielded first proof-of-principle results targeting HBV-positive tumours.


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12:30 Creating Focused Libraries for Protein Sponsored by Engineering Nels Thorsteinson, Scientific Services Manager, Biologics, Chemical Computing GroupProtein engineering plays a pivotal role in modulating the function, activity and physical properties of biologics. Representative strategies employed in protein engineering include directed evolution and rational protein design. Although both approaches are effective at identifying and optimizing protein therapeutic candidates, efficient search and evaluation of an excessively large sequence design space becomes challenging and requires multiple experimental rounds to reasonably assess the sequence space. Here we have developed a computational approach which predicts mutation probabilities for given residue sites in specified sequences. In assessing the probabilities at given residue sites, the sequence search space can be efficiently sampled to design and produce focused mutant libraries.

12:45 Enjoy Lunch on Your Own

13:30 Session Break

TARGET SELECTION AND SPECIFICITY

14:00 Chairperson’s RemarksUlrich Brinkmann, Ph.D., Expert Scientist, Roche Pharma Research & Early Development, Roche Innovation Center, Penzberg

14:05 Improved Binder Specificity by Using Structural Epitope RecognitionJonas V. Schaefer, Ph.D., Head, High-Throughput Binder Selection Facility, Biochemistry, University of ZurichSpecificity is a major challenge in the usage of affinity reagents for both therapeutic and diagnostic applications. Using our binder selection pipeline and novel ways of target presentation, we were able to tackle this issue. I will present data on ongoing projects targeting viral infections and neurodegenerative diseases, two fields of applications where target conformation is of critical importance.

14:35 The Use of Serum Compatibility to Select Bispecific AntibodiesMark Chiu, Ph.D., Associate Director, Multispecific Biologics Engineering, Biologics Research, Janssen Research & Development LLCBispecific antibody (bsAb) engineering can change protein symmetry and consequently molecular properties. Characterisations of bsAb in the presence of sera can assess potential self-interaction and interactions between the molecule and serum proteins which can affect PK, efficacy, aggregation, and immunogenicity. We present in vitro biophysical characterisations using spectroscopy and chromatography that can be used in developability to support lead selection.

15:05 High Throughput Approach to Select Synergistic Target Pairs and Bispecific AntibodiesJijie Gu, Ph.D., Senior Principal Research Scientist, Global Biologics, AbbVie Bioresearch CenterBispecific antibodies have emerged as one of the important approaches for next generation antibody-based therapeutics. One of the key challenges the bispecific antibody field is facing is how to identify target pairs and bispecific molecules with novel biology. This presentation will discuss a high-throughput approach to identify target pairs and bispecific antibodies with potential synergistic effect.


BISPECIFICS FOR IMMUNO-ONCOLOGY

16:15 Bispecific Anticalin Fusion Proteins for Localised Targeting of Immune Cells for Application in Immuno-OncologyChristine Rothe, Ph.D., Vice President, Discovery & Alliance Management, Pieris Pharmaceuticals, Inc.Anticalin® proteins are derived from human lipocalins and are about 18 kDa in size. We have generated different bispecific constructs by fusing distinct Anticalin proteins to each other or by fusing Anticalin proteins to antibodies or Fc-domains. These constructs simultaneously bind a tumour and a T cell target and may be able to better control T cell activation in the tumour mircoenvironment. Binding properties, stability and in vitro functionality of bispecific Anticalin fusion proteins are presented.

16:45 The Dual-Dual-Targeting Concept - Enhancing Natural Killer Cell-Mediated Lysis of Lymphoma Cells by Combining Therapeutic Antibodies with Bispecific Immunoligands Engaging NKG2D or NKp30Matthias Peipp, Ph.D., Group Leader, Stem Cell Transplantation and Immunotherapy, Christian-Albrechts-University of KielNovel bispecific immunoligands were compared for their abilities to boost ADCC in an attempt to design an effective antibody combination strategy. Co-targeting and activating NK cell receptors may represent a promising approach for enhancing the efficacy of therapeutic antibodies. A ‘dual-dual-targeting’ concept by co-targeting two tumour antigens and concomitant engagement of two different activating NK cell receptors is proposed.


Table 13: Comparing Bispecific Antibody Platforms: Key FeaturesModerator: Janine Schuurman, Ph.D., Vice President, Research, Genmab B.V.

Table 14: Benefits of Bispecifics over Combination TreatmentsModerators: Krzysztof Masternak, Ph.D., Head, Biology, Research, Novimmune SASarah Batey, Ph.D., Principal Scientist, Tumour Biology and Protein Science, F-star Biotechnology Ltd

Table 15: Improved Methods for Binder Screening and ValidationModerator: Jonas V. Schaefer, Ph.D., Head, High-Throughput Binder Selection Facility, Biochemistry, University of Zurich


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18:15 Networking Reception in the Exhibit Hall with Poster Viewing

19:15 End of Day

THURSDAY, 5 NOVEMBER

08:00 Morning Coffee

NOVEL APPROACHES FOR ONCOLOGY

08:30 Chairperson’s RemarksJanine Schuurman, Ph.D., Vice President, Research, Genmab B.V.

08:35 Exploiting the Versatility of Alphabodies to Target the Intrinsic Pro-Survival Protein MCL-1Yvonne McGrath, Ph.D., CSO, Complix NVAlphabodies are stable proteins where 70% of residues are amenable to modification by design or library selection. These features have been exploited in the design of Alphabodies which target the intracellular intrinsic pro-survival protein MCL-1. These Alphabodies have been shown to bind specifically to MCL-1 with high affinity and crystal structures obtained. Efficient uptake of the Alphabodies into cells and cell killing of MCL-1 dependent tumour cells has also been demonstrated.

09:05 An Engineered Fc Fragment Targeting HER2 Induces Profound Anti-Tumour Effects through ApoptosisSarah Batey, Ph.D., Principal Scientist, Tumour Biology and Protein Science, F-star Biotechnology Ltd.FS102 is a HER2 specific Fcab™ (Fc fragment with antigen binding) that induces profound HER2 degradation and potent cell apoptosis in tumour cells expressing high levels of the receptor. The efficacy of FS102 in patient-derived xenograft (PDX) models correlates strongly with clinically relevant HER2 biomarkers. We hypothesise that FS102 depletes HER2 which commits the HER2-addicted tumour cells to apoptosis through oncogenic shock. FS102 is currently in Phase I clinical trials.

09:35 Hapten-Directed Spontaneous Disulfide Shuffling: A Universal Technology for Site-Directed Covalent Coupling of Payloads to AntibodiesUlrich Brinkmann, Ph.D., Expert Scientist, Roche Pharma Research & Early Development, Roche Innovation Center, PenzbergHapten-binding antibodies with accessible cysteine in proximity to the binding pocket were designed to covalently attach payloads to the antibody. Payloads carrying thiols become positioned on the antibody and linked by spontaneous redox shuffling. Attachment works with different haptens, antibodies and payloads. Applications include modulation of pharmacokinetics of small compounds as well as payload linkage to targeting vehicles in a reduction-releasable manner.

10:05 An Integrated Approach to Managing Sponsored by Immunogenicity Risk and Drug Immune ModulationJeremy Fry, DPhil, Director, Sales, ProImmuneImmunogenicity is one of the most complex issues to address in drug design and development. I will provide an overview of the best tools to mitigate immunogenicity risk, including Mass Spectrometry antigen presentation assays; DC-T and T cell proliferation assays for biologic lead selection/optimization; HLA-peptide binding assays to characterize individual epitopes as well as undiluted whole blood cytokine storm assays.


BISPECIFICS FOR ONCOLOGY

11:15 Anti-CD20/CD3 T Cell Dependent Bispecific Antibody (TDB) as Potential Therapy for B Cell MalignanciesLaura Sun, Ph.D., Senior Research Associate/Project Lead, Translational Oncology, Genentech, Inc.The preclinical development of a B cell targeting anti-CD20/CD3 T-cell dependent bispecific antibody (CD20-TDB) will be described. CD20-TDB is highly active in killing B cells in vitro and in vivo as demonstrated in multiple murine models. In cynomolgus monkeys, CD20-TDB potently depletes B cells in peripheral blood and lymphoid tissues while demonstrating PK properties similar to those of conventional monoclonal antibodies.

11:45 Impact of Bispecific and Multi-Specific Molecule Structure on Safety and EfficacyTariq Ghayur, Ph.D., Distinguished Research Fellow, DVD-Ig and Novel Biologics, Global Biologics, AbbVie, Inc.Bi- and multi-specific formats differ in their target binding domain placement, distance and valency. These differences may be critical when targeting cell surface receptors. Therefore, designing the right format to match target and / or target pair biology may be important for selecting therapeutic candidates with desired safety, efficacy and PK profiles.



13:30 End of Bispecifics and Novel Products


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5-6 November 2015 | THIRD ANNUAL

Cancer BiotherapeuticsImmunotherapies, ADCs, and Combination Approaches

Recommended Short Course*

SC7: Immunotherapy in the 21st Century: More Specificity, More Potency; Better Targeting(*Separate registration required. Please see page 3 for more details.)


12:30 Registration


ADOPTIVE T CELL THERAPY

13:30 Chairperson’s Opening RemarksRakesh Dixit, Ph.D., Vice President, Safety Assessment, MedImmune (A member of AstraZeneca)

»KEYNOTE PRESENTATION13:35 Cancer Therapy by T Cell-Engaging Antibody Constructs

Tobias Raum, Ph.D., Scientific Director, Lead Generation, AMGEN Research (Munich) GmbHBispecific T cell-engaging (BiTE®) antibody constructs can transiently link tumour cells with otherwise inactive cytotoxic T cells for induction of

potent redirected lysis of attached tumour cells. One example is blinatumomab (AMG 103), a CD19/-CD3-bispecific BiTE® antibody construct for the treatment of acute lymphocytic leukaemia (ALL) and non-Hodgkin’s lymphoma (NHL), which has been filed in the EU for treatment of relapsed/refractory ALL, and approved in the US by the FDA in December 2014.

14:20 Bispecific Antibodies for Redirecting T-Cell Killing: Ag and Ab Factors Affecting the Killing PotencyDiego Ellerman, Ph.D., Senior Research Associate, Protein Chemistry, Genentech, Inc.T cell redirected cell killing is an expanding therapeutic approach in oncology. Bispecific antibodies targeting both the T cell receptor and a tumour-specific antigen are being developed for this approach. This presentation will explore the influence of antigen density, antibody affinity and epitope distance to the membrane on the antibody potency using Her 2 and other antigen models.

14:50 Cancer Biotherapeutics - Affimers: A Novel Sponsored by Scaffold for Biotherapeutics Amrik Basran, Ph.D., CSO, Therapeutics, Avacta LifesciencesAffimers are a new protein scaffold with great potential for the generation of biotherapeutics. Based on the protease inhibitor Stefin A, large diverse libraries have been created by engineering in peptide loops into the scaffold backbone. Using phage display, we have identified competitive binders to a ranage of targets, including the immune check point, PD-L1. We have shown that the scaffold is amenable to being engineered with a range of half-life extension technologies, giving “IgG like” PK.


16:05 A Novel T Cell-Engaging Bispecific Format with Full-Length Antibody Properties - Applications in Cancer ImmunotherapySeung Y. Chu, Ph.D., Associate Director, Cell Biology, Xencor, Inc.Bispecific antibody-mediated coengagement of T cells with tumour antigens is now a proven therapeutic strategy, but inferior stability, production and half-life have hindered clinical development. We have engineered modular Fc-containing bispecifics linking a portable CD3 with full-length antibodies against many tumour antigens. I will present development case studies of several bispecifics, showing superior pharmacology and half-life in monkeys plus efficient manufacturing.

16:35 Immtacs: Bi-Specific TCR-Based Reagents for Targeted Cancer ImmunotherapyJoseph Dukes, Ph.D., Head, Preclinical Biology, Cell Biology, Immunocore Ltd.ImmTACs are a novel class of soluble bi-specific reagents that exploit the natural antigen recognition pathway mediated by the T cell receptor (TCR), fused to a powerful effector function (anti-CD3) to redirect T-cell activity against tumour cells. This presentation will introduce the ImmTAC platform and the latest clinical data from our lead candidate, IMCgp100, currently in a Phase I/IIa trial for the treatment of malignant melanoma.

17:05 End of Day

17:00 – 17:30 Dinner Short Course Registration*SC7: Immunotherapy in the 21st Century: More Specificity, More Potency; Better Targeting(*Separate Registration Required. Please see page 3 for more details)

FRIDAY, 6 NOVEMBER

IMMUNE CHECKPOINTS07:30 Morning Coffee

08:00 Chairperson’s RemarksStephen Beers, Ph.D., Associate Professor, Cancer Sciences Unit, Faculty of Medicine, University of Southampton

08:05 Combinations of Check-Point Inhibitors with the First-in-Class Therapeutic NK-Cell Binding TandAb AFM13 (CD30/CD16A)Martin Treder, Ph.D., CSO, AffimedThe tetravalent bispecific TandAb AFM13 recruits and activates NK cells by specific binding to CD16A and mediates potent lysis of CD30+ tumour cells. Given promising clinical safety and efficacy data and the mechanistic involvement of immune effector cells, potential synergy with various check point inhibitors was investigated pre-clinically and will be presented.


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Cancer BiotherapeuticsImmunotherapies, ADCs, and Combination Approaches

08:35 Innovations in Cancer Biotherapeutics: Immune Checkpoint Antagonists, Agonists and CombinationsRakesh Dixit, Ph.D., Vice President, Safety Assessment, MedImmune (A member of AstraZeneca)The approval of one CTLA-4 and two PD-1 immune checkpoint antagonistic cancer biotherapeutics has rejuvenated the innovations in discovering and developing new immunotherapies that could increase responses and delay cancer associated deaths. The presentation will discuss the innovations in new immune checkpoint antagonists and agonists that show great promise in revolutionising cancer treatments.

09:05 T-DM1 Reinstates Anti-Tumour Immunity in HER2-Positive Breast Cancer: Synergies with α-CTLA-4 and α-PD-1Philipp Müller, Ph.D., Project Leader, Biomedicine, University Hospital of BaselADCs such as the HER2-directed antibody-maytansinoid conjugate T-DM1 have emerged as one of the most powerful therapeutic formats for cancer therapy. In this presentation I will demonstrate that T-DM1 is particularly effective in eliciting anti-tumour immune responses in breast cancer patients and a HER2-expressing, syngeneic and orthotopic tumour model. Our data reveal a novel immunological mechanism of action for T-DM1 and provide a strong rationale for clinical combinations with immunotherapies.


Table 22: Enhancement of Potency for Redirected T Cell KillingModerator: Seung Y. Chu, Ph.D., Associate Director, Cell Biology, Xencor, Inc.

Table 23: Safety Risks of Immunotherapy Combinations: Risk Mitigation StrategiesModerator: Rakesh Dixit, Ph.D., Vice President, R&D, Safety Assessment, MedImmune, Inc.

Table 24: Technologies for the Construction of Next-Generation ADCsModerator: Vijay Chudasama, Ph.D., Lecturer, Chemistry, University College London

10:35 Coffee Break with Poster Viewing

IMMUNOMODULATORY MECHANISMS / CHIMERIC ANTIGEN RECEPTOR THERAPY

11:00 Understanding How Isotype Determines the Mechanism of Action of Immunomodulatory Antibodies in the Treatment of CancerStephen Beers, Ph.D., Associate Professor, Cancer Sciences Unit, Faculty of Medicine, University of SouthamptonClinical results with checkpoint-blocking mAb have revived the belief that the immune system holds the key to controlling cancer. Here we show that immunostimulatory mAb can employ multiple mechanisms in tumours, and that the mechanism used depends on mAb isotype and FcγR availability. These data have broad implications for developing immunomodulatory mAb; illustrating the necessity to determine all potential mechanisms of action to maximise activity.

11:30 A Novel IgG-Based T Cell Bispecifics Platform Christian Klein, Ph.D., Head, Oncology Programs, Roche Pharmaceutical Research & Early Development, Roche Innovation Center ZurichThe presentation will introduce a novel IgG-based T cell bispecific (TCB) antibody platform enabled by the CrossMAb technology. Engineering, design and advantages as compared to existing T cell bispecifics platforms will be discussed. As a case study the preclinical properties of the CEA-CD3 TCB (RG7802) that is currently in Phase 1 clinical trials will be discussed.

ADC / IMMUNE CHECKPOINT COMBINATION

12:00 Chimeric Antigen Receptor Re-Directed T Cell Therapy: Biomarkers Lead the WayJ. Joseph (Jos) Melenhorst, Ph.D., Director, Product Development & Correlative Sciences, Center for Cellular Immunotherapies, University of PennsylvaniaT cells equipped with chimeric receptors (CAR) targeting tumours have evolved rapidly from a basic scientific tool to a new way in which we induce remission in patients with very poor risk cancer. The synergy between basic and translational science continues to further boost the utility of immunotherapy and enhance its potency in various forms of cancer. In my talk I will highlight recent developments in the field and conclude with how correlative studies may contribute to the success of this therapy.

12:30 Novel Cell-Based Bioassays for Analysis of Sponsored by mAb Fc Effector and Immune Checkpoint FunctionsVanessa Ott, Ph.D., Senior Product Manager, Promega CorporationBiologics development requires unique functional and analytical tools. We have developed reporter bioassays (e.g., ADCC, ADCP, PD-1/PD-L1) that overcome limitations of primary cell assays. The bioassays offer high specificity and sensitivity, broad linearity, and robust performance, and have been implemented in high-throughput settings for mAb development, potency and stability studies.


ADCs / ADC-BISPECIFIC COMBINATION

14:00 Chairperson’s RemarksPhilipp Müller, Ph.D., Project Leader, Biomedicine, University Hospital of Basel

14:05 A Plug-and-Play Approach to Antibody-Based Therapeutics via a Chemoselective Dual Click StrategyVijay Chudasama, Ph.D., Lecturer, Chemistry, University College LondonThere is clear demand for the construction of novel antibody-drug conjugate (ADC) platforms that offer greater stability, homogeneity and flexibility. A significant step towards the ideal platform for next generation antibody-based therapeutics is presented. Our technology provides decorated antibody constructs that are highly stable, with complete retention of antibody binding/structure post-modification. It combines site-specific functionalisation with exceptional versatility via a facile native disulfide targeted plug-and-play strategy.


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Cancer BiotherapeuticsImmunotherapies, ADCs, and Combination Approaches14:35 Targeting of Solid Tumours with Bi-Specifics and Bi-Specific ADCs to Induce Novel Biologics and Drug-Like PropertiesDavid Poon, Ph.D., Senior Director, External Research & Development and Alliances, Zymeworks, Inc.A robust, developable and manufacturable bi-specific platform will be discussed as the foundation to engineer novel anti-solid tumour antibodies. Unlike combination therapies, these bi-specifics demonstrate enhanced tumour decoration, tumour diffusion and retention, internalisation, and effector functions. Supported with IND-enabling in vivo efficacy studies, Zymeworks’ lead bi-specific and bi-specific ADC programs will be presented.

15:05 Improving Potency and Stability of Antibody-Drug ConjugatesPavel Strop, Ph.D., Associate Research Fellow, Protein Engineering, Rinat-PfizerTraditionally, most ADCs relied on chemical conjugation methods that yield heterogeneous mixtures of a variable number of drugs attached at different positions with an average of four drugs per antibody. The benefits of transglutaminase-based site-specific drug conjugation in terms of stability, manufacturing, improved therapeutic index and ability to generate high loaded ADCs will be discussed.

15:35 Advances and Applications of the Fleximer Platform Approach to ADCsTim Lowinger, Ph.D., CEO, Mersana TherapeuticsOne of the challenges in developing ADCs is achieving efficacy for low-expression targets. One approach to overcome this limitation has been developed at Mersana, utilising our unique Fleximer platforms. Examples and applications will be presented to highlight the benefits of this approach to achieve greater efficacy and therapeutic index for low expression.

16:05 Developability Assessment of ADCs – A Case StudyLars Linden, Ph.D., Head, Protein Biochemistry, Global Biologics, Cell and Protein Sciences, Bayer HealthcareDevelopability analysis of antibodies and ADCs determines, together with cell line productivity and cost-of-goods analysis, the manufacturing feasibility of a drug candidate. A thorough biochemical & biophysical characterisation is performed to analyse the intrinsic stability and technical robustness of clinical candidates. Standardisation is ensured by a check of platform compatibility (DSP and analytics).

16:35 End of Conference


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BIOLOGICS DEVELOPMENT STREAM

2-3 November 2015 | SIXTH ANNUAL

Optimisation and Development of BiologicsStrategies for Candidate Selection and Enhancement of Product Properties

Recommended Short Courses*

SC1: Engineering of Bispecific Antibodies

SC2: Mutation and Selection Strategies for Multi-Parameter Antibody Optimisation(*Separate registration required. Please see page 3 for more details.)

MONDAY 2 NOVEMBER


COMBINED KEYNOTE SESSION

13:40 PEGS Europe Team Welcome

13:45 Chairperson’s Opening RemarksDarrell Sleep, Director, Novozymes Biopharma R&D

13:50 Protein Engineering for New Modes of Actions and New Targets

Andreas G. Plückthun, Ph.D., Professor & Director, Biochemistry, University of ZurichUsing different display technologies and structure-based engineering, the possibilities of hitting extra- and intracellular targets will be

discussed, with an emphasis on extending the modes of action previously possible. The lecture will emphasise the need for interdisciplinary approaches.

14:30 Targeting Ion ChannelsTristan J. Vaughan, Ph.D., Senior Director, Antibody Discovery & Protein Engineering, MedImmune Ltd.Ion channels are complex integral membrane proteins that form a pore through which ions selectively pass down an electrochemical

gradient. They are prominent components of the nervous system where they can mediate transduction across synapses. Hence, certain channels represent good drug targets, especially for alleviating pain. Approaches will be described to target such ion channels with antibody-based drugs and a case study presented.

15:10 Current and Future Trends in Antibody TherapeuticsPaul W.H.I. Parren, Ph.D., Senior Vice President & Scientific Director, Preclinical Development & Research, GenmabTargeted treatment using antibody therapeutics has proved successful in the development of meaningful treatments in diverse

therapeutic areas. However, despite strong advances, many patients still fail to respond or become resistant to targeted treatment and novel innovative approaches to improve therapy are therefore required. Genetic and chemical engineering of antibodies, fueled by recent molecular insights, is providing important opportunities for the development of more potent antibody therapeutics. Examples from Genmab’s portfolio will be provided.


CANDIDATE SELECTION

16:30 Chairperson’s RemarksWilliam Finlay, Ph.D., Senior Director, Global Biotherapeutics, Pfizer, Inc.

16:35 Purpose Oriented Antibody Libraries for de novo Generation of pH-Dependent AntibodiesNicolas Fischer, Ph.D., Head, Research, Novimmune SASome antibodies having unique characteristics such as pH-dependent antigen binding are difficult to isolate using standard antibody generation platforms and thus require extensive engineering. We have created several purpose-oriented antibody libraries to facilitate the de novo isolation of candidates with characteristics such as pH-dependent binding or enzyme neutralisation activity.

17:05 Augmented Binary Substitution: Simultaneous Ultra-Humanisation, CDR Redundancy Minimisation and Stabilisation of Antibodies for Human TherapyWilliam Finlay, Ph.D., Senior Director, Global Biotherapeutics, Pfizer, Inc.This study presents a technology that generates stable, soluble, ultra-humanised antibodies via single-step CDR redundancy minimisation. For three antibodies from three separate key immune host species, ABS processing significantly lowered non-human sequence content, minimised T and B cell epitope risk in the final molecules and provided a heat map for the essential non-human CDR residue content of each antibody.

17:35 Veltis® Technology: Engineered Albumins for Sponsored by Optimized Serum Half-Life Extension Joanna Hay, Ph.D., Customer Solution Science Manager, Novozymes Biopharma UKShort circulatory half-life represents a major obstacle for many protein and peptide-based therapeutics, resulting in increased dosing with the consequent risk of side effects and reduced patient compliance. The half-life of therapeutic can be significantly improved by conjugation or fusion to albumin, due to both size and recycling via the neonatal Fc receptor (FcRn). We will describe rationally engineered albumins with increased FcRn affinity and their application to improve the pharmacokinetic properties of therapeutic candidates.




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TUESDAY, 3 NOVEMBER


OPTIMISATION OF AFFINITY, SPECIFICITY AND POTENCY

08:30 Chairperson’s RemarksNicolas Fischer, Ph.D., Head, Research, Novimmune SA

08:40 Design of Bispecific Antibodies: Target Biology Determines Optimal Valency of Binding SitesAlain C. Tissot, Ph.D., Head, Immune Biology, Large Molecule Research, Pharma Research and Early Development, Roche Innovation Center, PenzbergBispecific antibodies are attractive for multifactorial diseases and simplify development over combination therapies, particularly when the targets are two ligands. We provide data for two preclinical bispecific antibodies in RA targeting ligands, demonstrating the value of varying the valency of binding sites in order to fully exploit target biology and potency.

09:10 Exploiting the Advantages of Bicyclic Peptide TherapeuticsChristian Heinis, Ph.D., Professor, Institute of Chemical Sciences and Engineering, Ecole Polytechnique Federale de Lausanne (EPFL)My laboratory is developing antagonists based on bicyclic peptides by phage display. The bicyclic peptides combine key qualities of antibody therapeutics (high affinity and specificity) and advantages of small molecule drugs (access to chemical synthesis, diffusion into tissue, various administration options). An update on recently developed bicyclic peptides and their activities will be given.


Table 4: Alternative Protein Scaffolds: Lessons from the Past and Future ExpectationsModerator: Christian Heinis, Ph.D., Professor, Institute of Chemical Sciences and Engineering, Ecole Polytechnique Federale de Lausanne (EPFL)

Table 5: Engineering for OptimizationModerator: Laura Lin, Ph.D., Director, Global BioTherapeutic Technologies, Pfizer, Inc.

Table 6: Improving Therapeutic Antibody FormatsModerator: Paul W.H.I. Parren, Ph.D., Senior Vice President & Scientific Director, Preclinical Development & Research, Genmab B.V.


ENHANCEMENT OF CLEARANCE

11:20 pH and Calcium-Dependent Fully Human Biparatopic IgG Antibody for Efficient Elimination of Soluble Antigen from PlasmaEriko Murata, Master of Pharmacy, Research Scientist, Discovery Research, Chugai Pharmaceutical Co. Ltd.

We have previously shown that calcium-dependent antigen-binding antibody increases soluble antigen elimination by dissociating the antigen in the endosome. Here we report on a novel strategy to further accelerate antigen elimination from plasma in vivo. Identification and optimisation of calcium-dependent binding biparatopic antibody which forms multimeric antibody-antigen complexes to enhance binding to Fc receptors will be presented.

11:50 ARGX-113, A Novel Fc -Based Therapeutic Approach for Antibody-Induced PathologiesPeter Ulrichts, Ph.D., Senior Scientist, ArGEN-xARGX-113 is a proprietary antibody fragment based on arGEN-X’ ABDEG™ technology. ARGX-113 works by preventing pathogenic autoantibodies from being recycled, promoting their degradation and thereby clearing them from circulation. Preclinical data in cynomolgus monkeys proved ARGX-113 to be highly effective in rapidly eliminating pathogenic antibodies, while sparing the broader immune response. The data support further clinical development of this novel therapeutic approach in autoimmune disease management.

12:20 Epitope Binning, Mapping and Affinity Ranking Sponsored by of 96 Antibody SupernatantsRichard B.M. Schasfoort, Ph.D., CSO, IBIS Technologies B.V.The binding of an antibody to an epitope is innate and cannot be engineered anymore. Therefore the selection of antibodies that bind to the right functional epitope should be carried out as early as possible. Technology is now available enabling binning, mapping and affinity ranking of up to 96 Ab-sups in one unattended run.


14:00 Desert Break in the Exhibit Hall with Poster Viewing

DEVELOPABILITY ASSESSMENT AND PRECLINICAL EVALUATION

14:30 Chairperson’s RemarksFrank Walsh, CEO, Ossianix and Professor, Kings College London

14:35 Early Stage Developability Assessment of BiotherapeuticsLaura Lin, Ph.D., Director, Global BioTherapeutic Technologies, Pfizer, Inc.The presentation will describe an early stage molecular assessment platform we established in-house to rank, select, and optimise biotherapeutic leads in early discovery at Pfizer. I will be discussing our strategies of early screening for biophysical properties for a given project, and triage down a few leads for more in-depth developability assessment. I will share a specific case study highlighting developability comparisons between different modalities and the impact on efficacy, PK, and manufacturability.


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15:05 Preclinical Development of MGD010: A CD32BxCD79B Bispecific DART for the Treatment of Autoimmune Disease.Paul Moore, Ph.D., Vice President, Research, Cell Biology & Immunology, MacroGenics, Inc.MGD010, a bi-specific Dual-Affinity ReTargeting (DART) that inhibits B-cell activation via colligation of the inhibitory FcγRIIb receptor CD32B with the BCR component CD79B, is being developed as a novel therapeutic molecule for autoimmunity. Studies performed to support MGD010 clinical development will be presented, covering mechanism of action, therapeutic modeling, safety pharmacology and first-in-human dose projection

15:35 Preclinical Studies with FynomAbs, Fynomer-Antibody Fusion ProteinsVanessa Baeriswyl, Ph.D., Scientist, Covagen AG, one of the Janssen Pharmaceutical Companies of J&JBispecific FynomAbs are generated by fusing Fynomer binding proteins to antibodies. The ability to fuse Fynomers to multiple sites on the antibody allows the creation of therapeutics with higher potency and desired bioactivity, since the efficacy of bispecifics is greatly influenced by the orientation of the two binding sites relative to each other. Case studies of FynomAbs having selective tumour killing properties will be presented, as well as key parameters, such as manufacturability and yield (3.3 g/l obtained in 1000 liter GMP run), pharmacokinetics and stability.

16:05 Computational Advances in Antibody Design: Sponsored by Toward Improved Optimization and SelectionDavid Pearlman, Ph.D., Biologics, SchrödingerRecent computational advances hold significant promise both for improved prediction of antibody structure from sequence, and for the ability to precisely calculate physically relevant properties such as affinity and stability. When combined with additional theoretical approaches to identify liabilities, we can use these tools to variously optimize a lead antibody candidate and triage among multiple potential leads.


FORMULATION AND DELIVERY

17:15 Implementation of an Integrated High-Throughput Formulation Screening for BiologicsMichael Siedler, Ph.D., Section Head, NBE Formulation Sciences & Process Development, AbbVie Deutschland GmbH & Co KGModern formulation development increasingly relies on multivariate parameter analysis in order to enable statistical analysis. Consequently, the only way to generate and leverage the required vast amount of data is by applying appropriate scale-down methodologies and lab automation in conjunction with an IT infrastructure capable of transforming the data into knowledge. We will provide a case study of how this can be achieved.

17:45 Delivery of Single Domain Antibody Biotherapeutics to the Brain (NAB)Frank Walsh, CEO, Ossianix and Professor, Kings College LondonThis presentation will describe the development of a toolkit of individual single domain VNAR antibodies to the transferrin receptor 1 that bind with varying affinities to multiple epitopes on the receptor. These allow the generation of bispecific biotherapeutics that will cross the BBB via receptor-mediated endocytosis at therapeutic doses and can be tailor-made for differing therapeutic modalities. Studies showing direct translation from animal data to humans will be included.

18:15 Oral Delivery of Anti-TNF-Alpha Nanofitin Shows a Strong Preventive and Curative Anti-Inflammatory Effect in Models of Inflammatory Bowel DiseasesMathieu Cinier, Ph.D., Scientific Director, AffilogicDespite remarkable efficacy, treatment of IBD using systemic administration of anti-TNF-alpha antibodies remains associated with serious adverse effects. Extreme stability of the Nanofitins, novel alternative scaffolds, in the gut environment enable the development of orally available anti-TNF-alpha therapeutics and allow better targeting of the inflammation site while decreasing systemic exposure and related side effects.

18:45 End of Optimisation & Development


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Protein Aggregates and ParticlesTools and Techniques for Effective Prediction and Analysis of Aggregates and Particles


SC8: The Challenge of Protein Aggregation and Formation of Sub Visible Particles in the Development of Biopharmaceuticals

SC9: Advanced Techniques for Characterisation of Protein Aggregates, Particulates and Contaminants

(*Separate registration required. Please see Page 3 for more details.)



ENGINEERING PROTEIN THERAPEUTICS FOR REDUCED AGGREGATION

08:30 Chairperson’s Opening RemarksSalvador Ventura, Ph.D., Professor, Biochemistry and Molecular Biology, Institute of Biotechnology and Biomedicine, University of Barcelona

»KEYNOTE PRESENTATION08:35 Understanding (and Controlling) Aggregation of Antibody-Drug Conjugates

Fred Jacobson, Ph.D., Staff Scientist, Kadcyla™ Technical Development Leader, Protein Analytical Chemistry, Genentech, Inc.

09:20 Engineering Antibodies for Improved Developability Properties Chris Lloyd, Ph.D., Senior Scientist, Antibody Discovery and Protein Engineering, MedImmune

09:50 Stable Human Antibody Therapeutics and Phage Display Libraries through Engineering of Variable DomainsDaniel Christ, Ph.D., Associate Professor of Medicine; Head, Antibody Therapeutics, Immunology Program, Garvan Institute of Medical ResearchHuman antibody variable domains often display poor biophysical properties and a propensity to aggregate. We have identified aggregation hotspots in the CDR regions of antibody variable VH and VL domains, and have developed generally applicable strategies to overcome these limitations. Here we outline the application of the technology to human antibody therapeutics and antibody phage display libraries.

10:20 Innovative Technologies to Improve the Sponsored by Characterization of Protein AggregatesMatthew Brown, Ph.D., Scientist, Malvern Instruments Ltd.Understanding the process of protein aggregation is a key component of QbD approaches during biotherapeutic development or deviation resolution of legacy products. Advanced characterization technologies, now available to the biopharmaceutical industry, offer detailed insights into protein behavior to improve product stability and process knowledge and understanding.


IMPACT OF AGGREGATION ON FILLING AND FORMULATION

11:30 Challenges and Considerations Associated with Aggregation of Biopharmaceuticals during Fill Finish Process Development, Transfer and CommercialisationFrancis Carroll, Development Scientist, Technical Development, Genzyme Ireland Ltd.Fill Finish processing of biopharmaceuticals presents numerous challenges for the inhibition of aggregation. During filling operations, degradation induced by shear stress, chemical and photo exposure, manifests itself in elevated levels of HMWS. Furthermore, control of excipient state during lyophilisation is critical for maintaining a protein in its native state, which can inhibit increases in aggregation during a product’s shelf life.

12:00 Formulation Development Based on Sub-Visible Particle Morphology Using Micro-Flow ImagingMalin Persson, Ph.D., Senior Research Scientist, Biopharm Formulation Development, Novo Nordisk A/S

12:30 Simultaneous Detection of Protein Aggregation Sponsored by & Affinity Measurements in a Single SPR ExperimentAaron Martin, Senior Principal Scientist, Research & Development, SensiQ Technologies IncNo SPR-biosensor has been capable of delivering information on drug affinity and detect protein aggregates simultaneously in the same experiment. SensiQ Technologies presents data from a current collaboration with Genentech describing how this limitation can be eliminated via simultaneous detection of both protein aggregation and affinity determination in a single experiment as enabled by Pioneer FE SPR.


MECHANISM OF PROTEIN AGGREGATION

14:00 Chairperson’s RemarksJennifer McManus, Ph.D., Lecturer, Department of Chemistry, National University of Ireland Maynooth


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14:05 Understanding Protein Aggregation in Pharmaceutical ProductsAnkit Patel, Ph.D., Scientist, Late Stage Pharmaceutical Development, Genentech, Inc.Protein aggregates are common degradation products for therapeutic proteins. Due to the complex nature of protein aggregation, the underline mechanisms and their potential biological impacts are not always well understood. In this presentation, we will give an overview of protein aggregation phenomenon for a few pharmaceutical products. The mechanism and implication of these protein aggregates will be reviewed and discussed.

14:35 Aggregation Analysis at High and Low Protein ConcentrationsJennifer McManus, Ph.D., Lecturer, Department of Chemistry, National University of Ireland MaynoothAggregation of proteins may occur by a number of different mechanisms, which can lead to a range of aggregate types. Using a range of analytical techniques the formation of protein aggregates by various mechanisms has been assessed at low and where possible, at moderate to high protein concentrations. The effect of sugars on protein stability will also be discussed.

15:05 Effects of Protein Aggregation on Uptake, Processing and Presentation by Dendritic Cells – A Case StudyAnja Langenkamp, Ph.D., Principal Scientist, Immunopathology, Pharmaceutical Sciences, Roche Pharmaceutical Research & Early Development, Roche Innovation Center BaselStudies show that tolerance can be broken in transgenic mouse models by harshly stressed protein therapeutics. However, the underlying mechanisms and relevance for humans remain unclear. Thus, we studied the influence of aggregation on the uptake, presentation and activation of dendritic cells - the key regulators for adaptive immunity. First results will be presented that provide mechanistic insights into the properties of monomeric and aggregated variants of a therapeutic monoclonal antibody.


MODELING AND PREDICTION OF AGGREGATION PROPENSITY

16:15 Tuning the Aggregation Propensity of Protein StructuresSalvador Ventura, Ph.D., Professor, Biochemistry and Molecular Biology, Institute of Biotechnology and Biomedicine, University of BarcelonaThis talk presents a method to overcome the current limitations of predicting aggregation by sequencing. The AGGRESCAN3D (A3D) server overcomes the limitations by taking into account the protein structure and the experimental aggregation propensity scale. The identified aggregation-prone residues can be virtually mutated to design variants with increased solubility. Additionally, the A3D server takes into account the dynamic fluctuations of protein structure in solution, which may influence aggregation propensity.

16:45 Rational Design of Protein SolubilityMichele Vendruscolo, Ph.D., Professor, Department of Chemistry, University of CambridgeI will discuss the extent to which the solubility and aggregation of proteins are related to the physico-chemical properties of their amino acid sequences. Based on these properties, I will present methods for the prediction of the solubility and aggregation of proteins and illustrate how these methods can be of practical interest and importance.

17:15 Determinants and Impact of Antibody Aggregation on Production and ApplicationJoost Schymkowitz, Ph.D., Professor, VIB Switch Lab, Department of Cellular and Molecular Medicine, KULeuvenAs most proteins, antibodies have a propensity to aggregate that is determined by their primary sequence and aggregation acts as a bottleneck on both production and application. Accurate prediction of antibody quality is currently lacking but would be of value to help identify good antibodies. I will discuss a number of key determinants and how to employ them for this purpose.

17:45 Standards, Measurements, and Analysis for Protein Particle CharacterizationRichard Cavicchi, Ph.D., Scientist, Bioprocess Measurements Group, National Institute of Standards and TechnologyConcentration measurements of protein aggregates obtained on orthogonal instrument types often differ significantly. NIST is developing a protein aggregate standard that simulates aggregate properties for sizes from 1 µm to visible particles. In addition, we are using a custom microfluidic device that compares orthogonal measurements on single particles to analyze microfabricated particles of defined dimensions and protein aggregates to discern the effects of shape and porosity.


19:15 End of Day



METHODS FOR DETECTING, IDENTIFYING AND CHARACTERISING AGGREGATES & PARTICLES

08:30 Chairperson’s RemarksAntonio Ribeiro, Ph.D., Professor, Pharmaceutical Technology, University of Coimbra Azinhaga de Santa Comba

08:35 Nanoparticle Tracking Analysis for Studying Aggregation Profile of ParticlesAntonio Ribeiro, Ph.D., Professor, Pharmaceutical Technology, University of Coimbra Azinhaga de Santa CombaSubvisible particles do not constitute a mass fraction to be quantified by using size exclusion chromatography (SEC). Moreover, SEC requires high dilution of the


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sample, which itself can change the aggregation profile. Nanoparticle tracking analysis (NTA) can count and measure size individual species in undiluted particles and may be more appropriate than SEC for studying particles aggregation. Moreover, using fluorescent labeled particles, NTA may allow distinguishing individual from aggregated particles.

09:05 Hydrodynamic Diameter (By DLS) and Molecular Mass Measurement (By SLS After FFF) Can Characterise Aggregation Level of A HMW Protein Not Characterisable by SE-HPLCPeter Matthiessen, Ph.D., Senior Manager, Formulation, Fill/Finish, Baxter Innovations GmbHThe aggregation level of a HMW Protein cannot be quantified by SE-HPLC. Field flow fractionation can partially separate potential aggregates and SLS was used for quantitation of molecular mass increase. Also DLS was used to monitor hydrodynamic diameter increase by potential aggregates. Various temperature stress conditions in liquid and lyophilized form and mechanical stress by shaking or stirring, both known to induce aggregation, were investigated by DLS and SLS. The correlation of aggregation and subvisible particle levels was investigated.

09:35 New, Orthogonal Methods to Detect Protein Aggregation at High and Low ConcentrationTudor Arvinte, Ph.D., Chairman & CEO, Therapeomic, Inc.Based on case studies, different orthogonal methods will be presented that permit detection and characterisation of protein aggregates and particulate matter in liquid formulations of biopharmaceuticals at high and low a protein concentrations. A method alone cannot provide absolute information on the aggregates present in a sample. By using different methods to analyse a sample, we can obtain strong conclusions and a broad picture on the protein aggregation states and particulates present in the solutions.

10:05 Protein-Protein Interactions, in Multi Protein- Sponsored by Albumin or Peptide-Albumin Co-Formulations Using Recombinant Human Serum Albumin (rHSA) to Prevent AggregationDarrell Sleep, Director, R&D, Novozymes Biopharma It is well-known that rHSA has the ability to prevent protein and peptide aggregation. At drug concentrations <1mg/mL coating of hydrophobic and hydrophilic surfaces of the primary packaging material and process equipment is expected to prevent depletion and surface induced aggregation. When aggregation is independent of the surfaces (>1mg/mL) the mechanism of aggregation

prevention is less well understood and is likely to depend on the aggregation pathway of the drug. Some case studies suggest that hydrophobic patches on rHSA interact with hydrophobic patches on the drugs forming an rHSA-drug complex where such surface areas are shielded and hereby preventing self-association. Other case studies suggest an excluded volume effect with no rHSA-drug complex formation.


11:15 Detection and Characterisation of Visible, Sub Visible Particles and Other Aggregates: Achievements and ChallengesAnacelia Rios Quiroz, MSc, Late Stage Pharmaceutical and Process Development, Pharmaceutical Development & Supplies, PTD Biologics Europe, (PTDE-PF), F. Hoffmann-La Roche, Ltd.The talk will give an overview of required and commercially available counting methodologies for detection of protein aggregates and visible and sub visible particles (SbVP); species ubiquitously present in protein formulations. Focus will be SbVP as they are gaining attention regarding immunogenicity and quality attributes. Lack of a well-defined methodology for SbVP makes it important to increase our knowledge of emerging instruments’ performance. Applicability towards the assessment of a meaningful array of particle counting techniques will be discussed.

11:45 Chemical Kinetics and Microfluidic Sizing for the Analysis of the Aggregation of Therapeutic ProteinsPaolo Arosio, Ph.D., Marie Curie Postdoc Fellow, Department of Chemistry, University of CambridgeIn this presentation, we show how chemical kinetic analysis can identify the protein aggregation path-ways at the molecular level. We demonstrate the potential of this approach by analyzing the aggregation mechanisms of different IgGs and of human insulin under conditions that are relevant for downstream and formulation. Finally, we show a novel microfluidic technique that enables the sizing of polydisperse protein samples under native conditions on a second timescale.



13:30 End of Protein Aggregates & Particles


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Analytical Characterisation of BiotherapeuticsMethods & Strategies for Better Developability and Manufacturability of Molecules






12:30 Registration


13:30 Chairperson’s Opening RemarksRoman A. Zubarev, Ph.D., Professor, Division of Chemistry I; Head, Departmentof Medical Biochemistry & Biophysics, Karolinska Institutet

»KEYNOTE PRESENTATION13:35 Massive de novo Sequencing of IgG Variants in Human Blood by Mass Spectrometry

Roman A. Zubarev, Ph.D., Professor, Division of Chemistry I; Head, Department of Medical Biochemistry & Biophysics, Karolinska InstitutetThe traditional proteomics assay is complemented by profiling both IgGs and co-extracted proteins using de novo sequencing by HCD and ETD MS/

MS. Each of these two additional domains (IgGs and co-extracted proteins) adds at least as much information to patient stratification as the direct proteomics assay. New IgG peptides discovered by de novo sequencing contribute significantly to the predictive power of IgG-omics, and are potentially indicative of the disease etiology.

EARLY-STAGE VS. LATE-STAGE CHARACTERISATION

14:20 Biophysical Characterisation for Selection of Robust Humanised Therapeutic Antibody CandidatesAlison Turner, Group Leader, Biophysics, Biology, UCB CelltechPanels of humanised antibodies from UCB’s new Core Discovery Platform are transiently expressed and purified, then screened using a number of assays and biophysical techniques to select therapeutic candidates with optimal chemical and physical stability. This process provides early information on ‘manufacturability’ by reducing the aggregation risk during different purification steps (shear stress, buffer effects) and confidence in the stability of the drug product during storage and administration (high concentration effects).

14:50 Computational Approaches to Optimise Sponsored by Antibody Efficacy & Pharmaceutical Developability as Therapeutic AgentsAnne Goupil-Lamy, Principal Field Application Scientist, BIOVIA Science Council Fellow, BIOVIAWe will present how the convergence of BIOVIA capabilities supported by a common platform can be designed to help with the discovery and optimization of biotherapeutic candidates, in particular the management and analysis of all scientific and quality data generated throughout the process. We will highlight predictive analysis in Discovery Studio for early candidate selection and optimization. This includes high throughput antibody annotation and structure prediction, developability assessment to help improve stability, solubility and viscosity.


16:05 Characterisation of Acidic Species in Monoclonal AntibodyLi Zang, Ph.D., Senior Scientist, Analytical Development, BiogenAcidic species in monoclonal antibody are highly heterogeneous and challenging for detailed characterization. They may post impacts on the function and stability of the monoclonal antibody. A detailed characterization of acidic species in a monoclonal antibody biopharmaceutical will be presented in this talk. The potential impact of acidic species on function and stability of the antibody will be discussed.

16:35 Late-Stage Characterisation of a Therapeutic EnzymePeter Bernhardt, Ph.D., Senior Scientist, Analytical Development, ShireAn approach for late-stage characterization will be discussed that focuses on critical quality attributes. This approach includes developing a comprehensive understanding of product-derived substances and impurities formed during manufacturing and under relevant storage conditions, as well as structure elucidation of product variants and understanding of structure/function relationships. A complex glycoprotein used for enzyme replacement therapy will be used as an example.

17:05 End of Day

17:00 – 17:30 Dinner Short Course Registration*





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FRIDAY, 6 NOVEMBER


HIGH THROUGHPUT CHARACTERISATION AND BIOASSAY DEVELOPMENT

08:30 Chairperson’s RemarksVishal Kamat, Ph.D., Scientist, Biomolecular HTS Center, Therapeutic Proteins, Regeneron Pharmaceuticals

08:35 High-Throughput Label-Free SPR Binding Kinetics Assay for the Characterisation of Fully Human Therapeutic AntibodiesVishal Kamat, Ph.D., Scientist, Biomolecular HTS Center, Therapeutic Proteins, Regeneron PharmaceuticalsMost of the biosensors today have limited throughput capacity and are unconducive to perform high-throughput affinity screening of mAbs. In an effort to support Regeneron’s therapeutic antibody drug discovery, we have successfully optimized the affinity screening methods to expand the throughput capability using Biacore 4000 and MASS-1, beyond originally anticipated from these two instruments. Strategies adopted to increase throughput and comparability of the binding rates constants measured using this modified techniques will be presented.

09:05 Analysis of Classical and Novel Biotherapeutics with High-Throughput MCE AssaysStefanie Wohlrab, Ph.D., Post-Doc, Pharma Technical Development, Roche Diagnostics GmbHContinuous process automation and Design of Experiments (DoE) increase the number of samples that need to be processed. Microchip capillary electrophoresis (MCE) provides a high-throughput platform to monitor product quality. Here, we demonstrate the use of Perkin Elmer´s LabChip GXII platform to characterize as well as to monitor antibody fragments during bioprocessing. The MCE assay shows a good linear range, high sensitivity and provides a resolution superior to CE-SDS for some aspects.

09:35 Bioassays to Quantify a Therapeutic Fc-Fusion Protein in Preclinical StudiesKelly Loyet, Ph.D., Scientist, Biochemical and Cellular Pharmacology, Genentech, Inc.Pre-clinical studies were performed to evaluate the pharmacokinetics and efficacy of a potential therapeutic Fc-fusion protein. This talk will summarize the development of bioassays to quantify the pharmacokinetics of the therapeutic protein as well as markers of its pharmacodynamics. Due to a large number of studies performed and low concentration dosing groups, assays were optimized for efficiency and sensitivity. Both mouse and cynomolgus monkey studies will be discussed.

10:05 Trending and Statistical Tools for the Consistent Monitoring of Bioassay CharacteristicsErica Bortolotto, Ph.D., Scientist, Bioassay Development, Analytical Sciences for Biologics, UCB Pharma SAHow to monitor a method’s performance over time? Which parameters should be trended? How to ensure a continuous validation of the method or the assessment of the right concentration for critical reagents or the bridging between reference standards? This talk will present an overview of the problems via case studies presenting trending and statistical tools.


CHARACTERIZATION OF COMPLEX MOLECULES AND NOVEL FORMATS

11:00 Method for Postsynthetic Characterisation of Multi Antibody Polymalic Acid ConjugatesEggehard Holler, Ph.D., Professor & Research Scientist III, Neurosurgery, Cedars-Sinai Medical CenterThe method enables us to characterize arrays of multiple different antibodies covalently attached to biopolymalic acid based multifunctional nanoconjugates. The technology applies mild ammonolysis for cleavage which leaves proteins in their native state. Antibody content and multiple target (antigen) binding activities are validated by antibody structure and target (antigen) binding analysis using quantitative ELISA and size exclusion HPLC before and after specific cleavage and degradation of the polymalic acid platform.

11:30 Analytical Methods to Characterise BispecificsSamadhi Vitharana, Ph.D., Principal Scientist, Core Sciences & Technology, Takeda CaliforniaBispecific antibodies (BsAbs) targeting multiple antigens are one of the most dynamic classes of protein therapeutics in the pharmaceutical industry. Due to the complexities associated with production and purification processes of this therapeutic modality, it is important to first assess developability based on purity, functionality, homogeneity, thermal stability, and other important biophysical properties. This presentation will discuss analytical approaches to effectively investigate these developability and manufacturability properties of BsAbs.

12:00 Understanding Size Dependence of Rabbit Vitreal ClearanceWhitney Shatz, Ph.D., Senior Research Associate, Protein Chemistry, Genentech, Inc.Due to the relatively rapid clearance of protein drugs from the eye following intravitreal administration, maximal efficacy requires frequent dosing, typically monthly or bi-monthly. Although there is some data suggesting molecular weight (MW) may be important to vitreal clearance and ocular tissue distribution, systematic protein studies have not been performed. Using a rabbit ocular model, we tested this hypothesis to further our understanding of ocular pharmacokinetics.


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12:30 High-Throughput Characterisation of Sponsored by Monoclonal Antibodies Using the Fortebio Octet HTXJesper Pass, Ph.D., Principal Scientist, Novo Nordisk A/SIn order to meet an increasing demand for antibodies for therapeutic use and as research reagents, a state of the art automated workflow for high throughput generation of monoclonal antibodies (mAbs) has been established. With an increase in the number of antibodies generated, comprehensive characterization of large panels of antibodies is essential to ensure early selection of mAbs with the desired properties for further development. In order to ensure high throughput characterization, we utilize label-free Bio-Layer Interferometry (BLI) analysis performed on a Fortebio Octet HTX instrument. The Octet HTX has been implemented in the screening for specific binders, and characterization of selected mAbs with regards to affinity and epitope binning. The instrument is further used for selection and prioritization of high expressing clones in production cell-line development. Examples of the use of the Octet HTX in the automated high throughput mAb generation process will be presented.


13:30 Session Break

NEW APPROACHES AND NOVEL TECHNIQUES FOR PRODUCT AND PROCESS CHARACTERISATION

14:00 Chairperson’s RemarksHuijuan Li, Ph.D., Director, Analytical Development, Biologics Bioprocess Development, Merck Research Laboratories

14:05 Multi-Angle Effector Function Analysis of Human Monoclonal IgG GlycovariantsTilman Schlothauer, Ph.D., Senior Scientist, Biochemical and Analytical Research, Large Molecule Research, Roche Pharma Research and Early Development (pRED), Roche Innovation Center PenzbergTo assess Fc functionality, many different approaches for characterization exist, more or less reflecting the physiological mechanism of Fc receptor recruitment. Here we combined different ways to measure Fc functionality. In addition to classical antibody Fc receptor interaction studies of eight different enzymatically engineered IgG1 glycosylation variants, we analyzed also the behavior of these variants as a preformed immune complex on the new developed Fc Receptor affinity chromatography.

14:35 High-Throughput Glycoprofiling via glyXbox: A High-Performance Glycoanalysis-System Based On xCGE-LIFErdmann Rapp, Dr. rer.nat., Head, Bio/Process Analytics, Max Planck Institute for Dynamics of Complex Technical SystemsWe have developed a glycoanalysis approach, based on multiplexed capillary gelelectrophoresis with laser induced fluorescence detection (xCGE-LIF), which shows high potential for high-performance analysis of glycoconjugates. The

applicability of the system is demonstrated for different types of glycosamples (biopharmaceuticals, vaccines, human milk and blood serum). This novel modular high-performance glycoanalysis system allows fully automated, highly sensitive, instrument-, lab- and operator-independent “real” high-throughput glycoanalysis, a contrast to the prevailing costly and lab-space intensive methods.

15:05 Characterisation of Process Impurities, Product Variants, Post Translational Modifications for BiologicsHuijuan Li, Ph.D., Director, Analytical Development, Biologics Bioprocess Development, Merck Research LaboratoriesMultiple case studies will be discussed on characterization of recombinant monoclonal antibody (mAb) drugs and their degraded and/or post-translationally modified counterparts, drug product- related impurities and variants for successful development of biotherapeutics.

15:35 New Analytical Approaches in Process Development and Product CharacterisationAlok Sharma, Ph.D., Head, Analytical Development, Lupin PharmaceuticalsBiologics and biosimilars therapeutics have made significant foot-print in pharmaceutical industry. Due to patent exclusivities of early phase biological drugs are reaching to their end, lot of competition is growing to manufacture these off-patent biologics. As in case of biologics, “Process is the Product”, it becomes critically important to evaluate products manufactured by different routes. On the other, because of the complexity in structures and the structure–function relationship of biological therapeutics, such changes may lead to changes in molecular structures, which may adversely affect the quality, safety, or efficacy of the drug. Drug manufacturers must demonstrate the comparability of their products after process and formulation changes to ensure similar quality, safety, and efficacy. Biosimilars also require evaluation of their equivalency to the innovators’ products. By complementing traditional biochemical methodologies, biophysical characterization, using a variety of methodologies, can enhance product knowledge in terms of higher order structure, molecular size distribution, and the properties of aggregates. The state-of-the-art biophysical and structural techniques in comparability assessments provide critical insight in biosimilarity evaluation.

16:05 Exploring the Generation of Variants in QbDJames Sutter, MSc, MBA, Associate Manager, Biotech Process Sciences, Downstream Process, Merck SeronoThis talk will define QbD and its main components such as TPP, CQA, CPP, process characterisation, process & product knowledge, control strategy and design space. In the frame of QbD, optimising quality of biologics by generation, separation and characterisation of variants is key for product and process understanding. This presentation shows case studies on isolation and characterization of low & high molecular weight and charge antibody variants to explore various separation techniques for clearance.



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IMPURITIES & STABILITY STREAM

2-3 November 2015 | INAUGURAL

Protein Purification TechnologiesAchieving Purity & Quality

Recommended Short Course*SC4: Protein Purification Strategies: Dealing with Proteins that Are Prone to Aggregate

(*Separate registration required. Please see page 3 for more details.)

MONDAY, 2 NOVEMBER


COMBINED KEYNOTE SESSION13:40 PEGS Europe Team Welcome & Chairperson’s Opening RemarksMary Ann Brown, Executive Director, Conferences, Cambridge Healthtech InstituteMary Ruberry, Senior Conference Director, Cambridge Healthtech Institute

13:50 Streamlining Protein Expression & ProductionLorenz M. Mayr, Ph.D., Vice President & Global Head, Reagents & Assay Development, Innovative Medicines/Discovery Sciences, AstraZenecaUntil recently, protein expression has been seen as a rather mature business with well-established technologies and highly standardized processes for the production of recombinant proteins. Due to significant technological advancements in the field of transient gene expression (TGE), we need to change our perception. The field of mammalian transient gene expression has now started to become one of the most dynamic areas of modern biotechnology with a

steady flow of novel technologies and product innovations for the enhanced production of recombinant proteins in their native physiological environment, performed with high success rates and high yields.Lorenz Mayr will discuss the comprehensive and contemporary activities for transient gene expression at AstraZeneca. He will describe new developments around these technologies for the generation of high-performance protein expression systems.

14:30 Mechanically Refolding Proteins beyond Unboiling an EggGregory A. Weiss, Ph.D., Professor of Chemistry, Molecular Biology and Biochemistry, University of California, IrvineTraditionally, refolding proteins involves arduously optimising conditions to coax protein solution into thermodynamic equilibrium. Using a Vortex Fluid Device, my lab has applied shear stress during refolding to overcome barriers between protein folding states, rapidly driving refolding. For processes not dialysis-dependent, this accelerated refolding allows a more thorough search for conditions favoring protein stability. We have demonstrated VFD-based protein refolding on recombinant

proteins, plus refolded lysozyme from boiled egg whites.

15:10 INTERACTIVE PANEL DISCUSSION: Emerging Technologies and Methods to Improve YieldsNew technologies and approaches are leading to greater yields and greater efficiencies for analyzing quality. This panel discussion examines which technologies show the greatest promise, and discusses how these new methods will innovate the field of protein science. Discussion topics include:• High-throughput• Parallel expression/purification• Purity• Automation

• Protein folding• Assays• Cell line engineering

Moderator: Gregory A. Weiss, Ph.D., Professor of Chemistry, Molecular Biology and Biochemistry, University of California, IrvinePanelists:Ian Hodgson, Ph.D., BSc, Head, Molecular Biology, FUJIFILM Diosynth BiotechnologiesKyle J. Lauersen, Ph.D., Faculty of Biology, Algae Biotechnology & Bioenergy, Center for Biotechnology, Bielefeld UniversityDavid O’ Connell, Ph.D., Lecturer & Director, MSc Programmes inBiotherapeutics, Biomolecular & Biomedical Research, University College DublinSaurabh Sen, Ph.D., Principal Scientist, Immune Modulation and NBE Discovery,Boehringer Ingelheim Pharmaceuticals, Inc.


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PURIFYING ANTIBODIES

16:30 Chairperson’s RemarksDirk Linke, Ph.D., Professor, Molecular Microbiology, Biosciences, University of Oslo

16:35 Magnetically-Driven Hybrid Technologies for Antibody PurificationAna Cecília Afonos Roque, Ph.D., Assistant Professor, Chemistry, UCIBIO, Faculdade de Ciências e Tecnologia, Universidade Nova de LisboaTwo magnetically-driven hybrid technologies have been recently proposed by our group as novel alternatives for non-chromatographic antibody purification. One approach concerns with the incorporation of magnetic particles into macroporous structures to confer a magnetic response to the new composites. This magnetic response was explored for accelerated and efficient protein elution. In a second approach, the potential to combine aqueous two-phase extraction with magnetic separation was explored with success.

17:05 Purification of Common-Light-Chain Bispecific AntibodiesJuergen Nett, Ph.D., Associate Director, High Throughput Expression, Adimab LLCA variety of bispecific constructs benefit from the use of a single variable light region pairing with multiple distinct variable heavy regions. This talk will demonstrate new techniques to purify these common-light-chain bispecific IgG molecules to homogeneity. A panel of bispecific constructs are then generated that bind to each target with high affinity and exhibit favorable biophysical properties similar to traditional therapeutic antibodies.

17:35 Aqueous Two-Phase Systems: A New Platform for Antibody PurificationMaria Raquel Aires-Barros, Ph.D., Full Professor, Institute for Bioengineering and Biosciences, Bioengineering Department, Instituto Superior Técnico, Universidade de LisboaAqueous two-phase systems (ATPS) have proven to be a valuable option for the downstream processing of monoclonal antibodies (mAbs), combining a high biocompatibility and selectivity with an easy and reliable scale up and capability of continuous operation. A continuous process based in ATPS was developed by our group, for the capture of mAbs from mammalian cell culture supernatants. Furthermore, an ATPS microfluidic platform was designed as an effective tool to accelerate bioprocess design and optimization.’’



TUESDAY, 3 NOVEMBER


PURIFYING MEMBRANE PROTEINS

08:30 Chairperson’s RemarksKarin Felderer, Ph.D., Associate Director, Protein Production, Protein Sciences, MorphoSys AG

08:40 Bacterial Membrane Separation, Fractionation and Solubilization as Essential Steps in Membrane Protein PurificationDirk Linke, Ph.D., Professor, Molecular Microbiology, Biosciences, University of OsloWe strive to compare and improve different protocols for the fractionation of proteins from Gram-negative bacteria into outer membrane, cytoplasmic membrane, periplasmic, and cytosolic fractions. I will compare 5 methods for membrane fractionation, and will discuss downstream processing and protein purification. I will also show recent data on fluorescence labeling of different membrane systems, that we use to track yield and purity of our membrane samples.

09:10 GPCR Structural Biology: A Case Study with a Novel Fluorescent Fusion PartnerSaurabh Sen, Ph.D., Principal Scientist, Immune Modulation and NBE Discovery, Boehringer Ingelheim Pharmaceuticals, Inc.Structural biology of membrane proteins and GPCRs has seen major advances over the past few years, but overcoming the challenges of functional GPCR expression and structural stabilization are still time-consuming and expensive. The talk will focus on an approach that combines a powerful cloning strategy with novel transmembrane guides and a novel fluorescent reporter which significantly increases functional receptor expression in E. coli along with other downstream processing benefits.


Table 7: Bottlenecks in the Purification of BiotherapeuticsModerator: David O’Connell, Ph.D., Lecturer & Director, MSc Programmes in Biotherapeutics, Biomolecular & Biomedical Research, University College Dublin

Table 8: Systems for GPCR Expression: Have We Identified the Best Yet?Moderator: Saurabh Sen, Ph.D., Principal Scientist, Immune Modulation and NBE Discovery, Boehringer Ingelheim Pharmaceuticals, Inc.

Table 9: Transition of Projects from Discovery to Development: What are Important Points to Consider or Lessons Learned?Moderator: Stefan Schmidt, Ph.D., Vice President, Process Science & Production, Rentschler Biotechnologie GmbH



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AFFINITY PURIFICATION

11:20 Recombinant Production and Utilization of Affinity of ProteinsSophia Hober, Ph.D., Professor, Protein Technology, Biotechnology, KTH Royal Institute of TechnologyStrategies for optimization of protein production and purification will be presented as well as a miniaturized high throughput method for protein verification. Fusion tags for improved selectivity of protein purification processes including protein domains with dual affinity will be presented. The dual affinity design can be of advantage for protein purification as well as other applications where affinity to more than one target molecule can be of value. Moreover, a novel, affinity-based method, that renders site-specific labeling of antibodies possible will be discussed.

11:50 Application of a Novel Fragment Complementation-Based Affinity System for Improved Protein Purification in a Single Step – from Highly Soluble to Membrane Proteins and Therapeutic Binder MoleculesDavid O’ Connell, Ph.D., Lecturer & Director, MSc Programmes in Biotherapeutics, Biomolecular & Biomedical Research, University College DublinIn this presentation the performance of a novel EF hand-based fragment complementation system will be highlighted for the purification of GFP, carbonic anhydrase, GPCR and DARPin binder proteins. The application of a single-step purification rationale will be compared to tandem affinity purification approaches and downstream assays will be described.


13:20 Session Break


OVERCOMING PURIFICATION CHALLENGES

14:30 Chairperson’s RemarksDavid O’ Connell, Ph.D., Lecturer & Director, MSc Programmes in Biotherapeutics, Biomolecular & Biomedical Research, University College Dublin

14:35 Case Studies: IDPs “Intrinsically Disordered Proteins,” Difficult to Produce, but with a Significant Role in Cellular PathwaysMario Lebendiker, Ph.D., Head, Protein Purification Facility, Wolfson Centre for Applied Structural Biology, Institute of Chemistry, The Hebrew University of JerusalemDisordered domains in IDPs “Intrinsically disordered proteins” or IDRs “Intrinsically disordered regions” play a significant role in cellular pathways, with an enormous potential as medical targets. Because of their lack of stable tertiary structure and their dynamic interchanging extended and flexible conformations, these types of proteins are prone to aggregate, and constitute an extraordinary challenge to produce. We’ll briefly illustrate here our strategy to produce enough amounts of these type of targets for biophysical and biochemical studies that allows us to show the way by which such domains act.

15:05 High Yield Expression of Protein Kinases in Insect CellsSvend Kjaer, Ph.D., Head, Protein Purification, Structural Biology Science Technology Platform, Francis Crick InstituteBaculovirus mediated infection of insect cells is a well-established technology for production of proteins with many end-point applications. In this presentation, I’ll present data on the expression and purification of a kinase target and demonstrate the importance of co-expression strategies for downstream success. Moreover, data on a generic method, which significantly improves yields by infection of insect cell at high cell densities will be presented.

15:35 How to Get the High Hanging Fruits – Tools for Generation of Difficult-to-Express AntigensKarin Felderer, Ph.D., Associate Director, Protein Production, Protein Sciences, MorphoSys AGA critical but often unaccounted factor in successful discovery and development of therapeutic antibodies is the availability of high quality antigens and tool proteins in sufficient amounts. The presentation will focus on the development of a novel lysozyme-based expression/purification tag system allowing us to produce difficult-to-express proteins of high quality as soluble monomers. Diverse case studies on expression of human CD19, Fc receptors and other proteins will be presented.

16:05 Native and Stabilized Membrane Proteins Sponsored by for Drug DiscoveryAnass Jawhari, Ph.D., CSO, CALIXARCALIXAR has developed patented technology based on new chemistry approach to safely isolate membrane proteins (GPCR, ion channels, transporters, enzymes and viral proteins) for drug discovery (antibody development, ligand screening, SBDD and vaccine application). The presentation will illustrate some case studies including Adenosine receptor A2A that was solubilized and purified without any single mutation, truncation or fusion for antibody development purposes and crystallization.


INNOVATING PURIFICATION PROCESSES17:15 Robust Design of Continuous Purification of Adenovirus Vectors by Two-Column, Simulated Moving-Bed, Size-Exclusion ChromatographyJosé Paulo Mota, Ph.D., Professor, Chemical and Biochemical Engineering, Animal Cell Technology, iBET & FCT-Universidade Nova de LisboaA two-column simulated moving-bed (2CSMB) process for continuous purification of adenoviral vectors by size-exclusion chromatography is presented and validated experimentally, and a general procedure for its robust design under parameter uncertainty is described. The pilot-scale runs yield a virus recovery of 86% and impurity clearance of 90% without any fine-tuning of the operating parameters. This yield is 60% better and the productivity is increased by 6-fold with respect to single-column batch chromatography for the same volume of resin.


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17:45 Estimating Protein Phase Behavior Based on Osmotic Virial Coefficients – A Thermodynamics-Based ApproachChristian Kress, Dipl.-Ing, Scientist, Biochemical and Chemical Engineering, Laboratory of Thermodynamics, Technical University of BerlinCurrently product capturing within protein production is often based on Protein-A chromatography, limited in capacity and scalability, which leads to a demand for different workup strategies (e.g. extraction by ATPS or precipitation). In order to enable estimations on the applicability of these workup strategies, models to calculate partition coefficients or protein solubility are required. Therefore a new estimation strategy based on the second osmotic virial coefficients B22 and B23 is used.

18:15 Purification of Therapeutic Proteins under Cost ConstraintsStefan Schmidt, Ph.D., Vice President, Process Science & Production, Rentschler Biotechnologie GmbHBiologicals and biosimilars represent the fastest growing segment in the drug pipeline. This puts a lot of pressure on economical manufacturing, primarily solving efficiency issues in downstream processing. Here I demonstrate how to solve challenges by applying disposables, using modular concepts, replacing costly affinity resins and reducing the number of steps in platform processes. The case studies with examples from various molecule classes highlight successful process design, optimization strategies and critical manufacturing parameters.

18:45 End of Protein Purification Technologies


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ENGINEERING PROTEIN THERAPEUTICS FOR REDUCED AGGREGATION

08:30 Chairperson’s Opening RemarksSalvador Ventura, Ph.D., Professor, Biochemistry and Molecular Biology, Institute of Biotechnology and Biomedicine, University of Barcelona

»KEYNOTE PRESENTATION

08:35 Understanding (and Controlling) Aggregation of Antibody- Drug Conjugates

Fred Jacobson, Ph.D., Staff Scientist, Kadcyla™ Technical Development Leader, Protein Analytical Chemistry, Genentech, Inc.

09:20 Engineering Antibodies for Improved Developability Properties Chris Lloyd, Ph.D., Senior Scientist, Antibody Discovery and Protein Engineering, MedImmune

09:50 Stable Human Antibody Therapeutics and Phage Display Libraries through Engineering of Variable DomainsDaniel Christ, Ph.D., Associate Professor of Medicine; Head, Antibody Therapeutics, Immunology Program, Garvan Institute of Medical ResearchHuman antibody variable domains often display poor biophysical properties and a propensity to aggregate. We have identified aggregation hotspots in the CDR regions of antibody variable VH and VL domains, and have developed generally applicable strategies to overcome these limitations. Here we outline the application of the technology to human antibody therapeutics and antibody phage display libraries.

10:20 Innovative Technologies to Improve the Sponsored by Characterization of Protein AggregatesMatthew Brown, Ph.D., Scientist, Malvern Instruments Ltd.Understanding the process of protein aggregation is a key component of QbD approaches during biotherapeutic development or deviation resolution of legacy products. Advanced characterization technologies, now available to the biopharmaceutical industry, offer detailed insights into protein behavior to improve product stability and process knowledge and understanding.


IMPACT OF AGGREGATION ON FILLING AND FORMULATION

11:30 Challenges and Considerations Associated with Aggregation of Biopharmaceuticals during Fill Finish Process Development, Transfer and CommercialisationFrancis Carroll, Development Scientist, Technical Development, Genzyme Ireland Ltd.Fill Finish processing of biopharmaceuticals presents numerous challenges for the inhibition of aggregation. During filling operations, degradation induced by shear stress, chemical and photo exposure, manifests itself in elevated levels of HMWS. Furthermore, control of excipient state during lyophilisation is critical for maintaining a protein in its native state, which can inhibit increases in aggregation during a product’s shelf life.

12:00 Formulation Development Based on Sub-Visible Particle Morphology Using Micro-Flow ImagingMalin Persson, Ph.D., Senior Research Scientist, Biopharm Formulation Development, Novo Nordisk A/S

12:30 Simultaneous Detection of Protein Aggregation Sponsored by & Affinity Measurements in a Single SPR ExperimentAaron Martin, Senior Principal Scientist, Research & Development, SensiQ Technologies IncNo SPR-biosensor has been capable of delivering information on drug affinity and detect protein aggregates simultaneously in the same experiment. SensiQ Technologies presents data from a current collaboration with Genentech describing how this limitation can be eliminated via simultaneous detection of both protein aggregation and affinity determination in a single experiment as enabled by Pioneer FE SPR.



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MECHANISM OF PROTEIN AGGREGATION

14:00 Chairperson’s RemarksJennifer McManus, Ph.D., Lecturer, Department of Chemistry, National University of Ireland Maynooth

14:05 Understanding Protein Aggregation in Pharmaceutical ProductsAnkit Patel, Ph.D., Scientist, Late Stage Pharmaceutical Development, Genentech, Inc.Protein aggregates are common degradation products for therapeutic proteins. Due to the complex nature of protein aggregation, the underline mechanisms and their potential biological impacts are not always well understood. In this presentation, we will give an overview of protein aggregation phenomenon for a few pharmaceutical products. The mechanism and implication of these protein aggregates will be reviewed and discussed.

14:35 Aggregation Analysis at High and Low Protein ConcentrationsJennifer McManus, Ph.D., Lecturer, Department of Chemistry, National University of Ireland MaynoothAggregation of proteins may occur by a number of different mechanisms, which can lead to a range of aggregate types. Using a range of analytical techniques the formation of protein aggregates by various mechanisms has been assessed at low and where possible, at moderate to high protein concentrations. The effect of sugars on protein stability will also be discussed.

15:05 Effects of Protein Aggregation on Uptake, Processing and Presentation by Dendritic Cells – A Case StudyAnja Langenkamp, Ph.D., Principal Scientist, Immunopathology, Pharmaceutical Sciences, Roche Pharmaceutical Research & Early Development, Roche Innovation Center BaselStudies show that tolerance can be broken in transgenic mouse models by harshly stressed protein therapeutics. However, the underlying mechanisms and relevance for humans remain unclear. Thus, we studied the influence of aggregation on the uptake, presentation and activation of dendritic cells - the key regulators for adaptive immunity. First results will be presented that provide mechanistic insights into the properties of monomeric and aggregated variants of a therapeutic monoclonal antibody.


MODELING AND PREDICTION OF AGGREGATION PROPENSITY

16:15 Tuning the Aggregation Propensity of Protein StructuresSalvador Ventura, Ph.D., Professor, Biochemistry and Molecular Biology, Institute of Biotechnology and Biomedicine, University of BarcelonaThis talk presents a method to overcome the current limitations of predicting aggregation by sequencing. The AGGRESCAN3D (A3D) server overcomes the limitations by taking into account the protein structure and the experimental aggregation propensity scale. The identified aggregation-prone residues can be virtually mutated to design variants with increased solubility. Additionally, the A3D server takes into account the dynamic fluctuations of protein structure in solution, which may influence aggregation propensity.

16:45 Rational Design of Protein SolubilityMichele Vendruscolo, Ph.D., Professor, Department of Chemistry, University of CambridgeI will discuss the extent to which the solubility and aggregation of proteins are related to the physico-chemical properties of their amino acid sequences. Based on these properties, I will present methods for the prediction of the solubility and aggregation of proteins and illustrate how these methods can be of practical interest and importance.

17:15 Standards, Measurements, and Analysis for Protein Particle CharacterizationRichard Cavicchi, Ph.D., Scientist, Bioprocess Measurements Group, National Institute of Standards and TechnologyConcentration measurements of protein aggregates obtained on orthogonal instrument types often differ significantly. NIST is developing a protein aggregate standard that simulates aggregate properties for sizes from 1 µm to visible particles. In addition, we are using a custom microfluidic device that compares orthogonal measurements on single particles to analyze microfabricated particles of defined dimensions and protein aggregates to discern the effects of shape and porosity.

7:45 Oral Poster PresentationHigh Resolution Antibody Modeling Identifies “Design-able” AntibodyHiroki Shirai, Ph.D., Executive Fellow, Bioscience Research Laboratories, Astellas Pharma Inc.“Antibody informatics” can be considered as a set of technologies to select and/or design antibodies to remove various obstacles for drug discovery, and antibody modeling is the basis of all above(ref.1). In the course of drug discovery, researchers should select a limited numbers of lead antibodies to be optimized among many candidates, but the difficulty in antibody engineering sometimes depends on antibody sequence. If one can identify “design-able” antibodies which are easy to build models for design with high accuracy, it would be helpful for rational selection. We set up high resolution antibody modeling technology especially focused on CDR-H3 modeling by integrated approach by informatics and simulation(ref.2). It proved competitive at a world wide assessment(ref.2,3). We can predict “degree of accuracy” of model for the particular sequences. Based on the “accuracy prediction”, we can identify “design-able” antibodies. We are seeking some collaborators to maximize the benefit.


19:15 End of Day


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METHODS FOR DETECTING, IDENTIFYING AND CHARACTERISING AGGREGATES & PARTICLES

08:30 Chairperson’s RemarksAntonio Ribeiro, Ph.D., Professor, Pharmaceutical Technology, University of Coimbra Azinhaga de Santa Comba

08:35 Nanoparticle Tracking Analysis for Studying Aggregation Profile of ParticlesAntonio Ribeiro, Ph.D., Professor, Pharmaceutical Technology, University of Coimbra Azinhaga de Santa CombaSubvisible particles do not constitute a mass fraction to be quantified by using size exclusion chromatography (SEC). Moreover, SEC requires high dilution of the sample, which itself can change the aggregation profile. Nanoparticle tracking analysis (NTA) can count and measure size individual species in undiluted particles and may be more appropriate than SEC for studying particles aggregation. Moreover, using fluorescent labeled particles, NTA may allow distinguishing individual from aggregated particles.

09:05 Hydrodynamic Diameter (By DLS) and Molecular Mass Measurement (By SLS After FFF) Can Characterise Aggregation Level of A HMW Protein Not Characterisable by SE-HPLCPeter Matthiessen, Ph.D., Senior Manager, Formulation, Fill/Finish, Baxter Innovations GmbHThe aggregation level of a HMW Protein cannot be quantified by SE-HPLC. Field flow fractionation can partially separate potential aggregates and SLS was used for quantitation of molecular mass increase. Also DLS was used to monitor hydrodynamic diameter increase by potential aggregates. Various temperature stress conditions in liquid and lyophilized form and mechanical stress by shaking or stirring, both known to induce aggregation, were investigated by DLS and SLS. The correlation of aggregation and subvisible particle levels was investigated.

09:35 New, Orthogonal Methods to Detect Protein Aggregation at High and Low ConcentrationTudor Arvinte, Ph.D., Chairman & CEO, Therapeomic, Inc.Based on case studies, different orthogonal methods will be presented that permit detection and characterisation of protein aggregates and particulate matter in liquid formulations of biopharmaceuticals at high and low a protein concentrations. A method alone cannot provide absolute information on the aggregates present in a sample. By using different methods to analyse a sample, we can obtain strong conclusions and a broad picture on the protein aggregation states and particulates present in the solutions.

10:05 Protein-Protein Interactions, in Multi Protein- Sponsored by Albumin or Peptide-Albumin Co-Formulations Using Recombinant Human Serum Albumin (rHSA) to Prevent AggregationJens Thostrup Bukrinski, Ph.D., Senior Scientist, Biopharma R&D, Novozymes A/SIt is well-known that rHSA has the ability to prevent protein and peptide aggregation. At drug concentrations <1mg/mL coating of hydrophobic and hydrophilic surfaces of the primary packaging material and process equipment is expected to prevent depletion and surface induced aggregation. When aggregation is independent of the surfaces (>1mg/mL) the mechanism of aggregation prevention is less well understood and is likely to depend on the aggregation pathway of the drug. Some case studies suggest that hydrophobic patches on rHSA interact with hydrophobic patches on the drugs forming an rHSA-drug complex where such surface areas are shielded and hereby preventing self-association. Other case studies suggest an excluded volume effect with no rHSA-drug complex formation.


11:15 Detection and Characterisation of Visible, Sub Visible Particles and Other Aggregates: Achievements and ChallengesAnacelia Rios Quiroz, MSc, Late Stage Pharmaceutical and Process Development, Pharmaceutical Development & Supplies, PTD Biologics Europe, (PTDE-PF), F. Hoffmann-La Roche, Ltd.The talk will give an overview of required and commercially available counting methodologies for detection of protein aggregates and visible and sub visible particles (SbVP); species ubiquitously present in protein formulations. Focus will be SbVP as they are gaining attention regarding immunogenicity and quality attributes. Lack of a well-defined methodology for SbVP makes it important to increase our knowledge of emerging instruments’ performance. Applicability towards the assessment of a meaningful array of particle counting techniques will be discussed.

11:45 Chemical Kinetics and Microfluidic Sizing for the Analysis of the Aggregation of Therapeutic ProteinsPaolo Arosio, Ph.D., Marie Curie Postdoc Fellow, Department of Chemistry, University of CambridgeIn this presentation, we show how chemical kinetic analysis can identify the protein aggregation path-ways at the molecular level. We demonstrate the potential of this approach by analyzing the aggregation mechanisms of different IgGs and of human insulin under conditions that are relevant for downstream and formulation. Finally, we show a novel microfluidic technique that enables the sizing of polydisperse protein samples under native conditions on a second timescale.



13:30 End of Protein Aggregates & Particles


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Protein Formulation and StabilityOvercoming Formulation Challenges with Advanced Techniques and Proven Strategies


12:30 Registration


FORMULATION APPROACHES TO MINIMISE CHEMICAL DEGRADATION

13:30 Chairperson’s Opening RemarksElizabeth M. Topp, Ph.D., Dane O. Kildsig Chair and Head, Department of Industrial and Physical Pharmacy, Purdue University

»KEYNOTE PRESENTATION13:35 Light-Induced Degradation and Aggregation of Antibodies and Antibody Drug-Conjugates

Christian Schoneich, Ph.D., Takeru Higuchi Distinguished Professor and Chair, Department of Pharmaceutical Chemistry, University of KansasAntibody-drug conjugates (ADCs) provide a promising approach to deliver large payloads of toxic drugs. However, chemical and physical stability problems of ADCs may arise from the exposure of ADCs to

light, as several ADCs contain drug conjugates, which may act as photosensitizer and drug conjugation may change the general sensitivity towards light. This talk will focus on product formation and mechanisms of light-induced degradation of antibodies and model ADCs.

14:20 Practical Considerations in Screening Excipients for Protein DrugsAndrea Ji, Ph.D., Senior Scientist, Genentech, Inc.The presentation will address the critical factors to be considered in protein formulation development such as oxidation, deamidation and excipient degradation as well as mitigation strategies.

14:50 It’s Time to Start Dreaming About High Sponsored by Throughput Screening! Multiplex Your Measurements to Unlock Biologic StabilityDaniel Lund, Ph.D., Product Manager, Unchained Labs

The stability and characterization of biologics are crucial steps in the development of modern medicines. Screening for and optimizing conditions used by biologics can increase long-term stability and manufacturability. Bringing these measurements into the pre-formulation stage de-risks development and aids in the selection of the optimum candidate. However, achieving this has been challenging for many years due to the lack of high-throughput, low sample consumption analytical tools. The UNit, a unique and pioneering stability platform from Unchained Labs, overcomes these inadequacies and allow researchers to develop stable proteins in optimal formulations which can be more easily manufactured and stored for longer.


16:05 Rational ADC Formulation Design as a Tool to Prevent Chemical and Physical InstabilitiesJanet L. Wolfe, Ph.D., President, Wolfe Laboratories, Inc.Understanding of the multiple degradation pathways that an ADC can undergo will enable rational ADC formulation design. Such an approach requires an array of biophysical and analytical characterization techniques, and yields a de-risked development path that minimizes the timeline to clinical testing. A case study will be presented of formulation approaches that mitigate aggregation and chemical degradation pathways.

16:50 Selected Poster Presentation II:The Downstream Procedure from E.coli Influences Stability, Functionality and in vivo Biodistribution of CD44-Targeted Protein NanoparticlesMireia Pesarrondona, MSc., Nanobiotechnology Group, Institute of Biotechnology and Biomedicine of Autonomous University of BarcelonaProtein based nanoparticles are gaining interest in nanomedicine but protein stability and therefore activity might be sensitive to production conditions and purification strategies applied. How structure and biological performance of self-assembling CD44-targeted protein-only nanoparticles is affected by the downstream procedure is presented as a comparative analysis between particles purified from soluble cell fraction and protein versions obtained by in vitro extraction from inclusion bodies applying non-denaturant agents

17:05 End of Day



SC9: Advanced Techniques for Characterisation of Protein Aggregates, Particulates and Contaminants(*Separate registration required. Please see Page 3 for more details.)



SC9: Advanced Techniques for Characterisation of Protein Aggregates, Particulates and Contaminants(*Separate registration required. Please see Page 3 for more details.)


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FRIDAY, 6 NOVEMBER


FORMULATION CONSIDERATIONS FOR EXISTING AND EMERGING BIOMOLECULES

08:30 Chairperson’s RemarksAjit Narang, Ph.D., Principal Scientist, Drug Product Science and Technology, Bristol-Myers Squibb

08:35 Technical Development Considerations in the Design of Parenteral Protein SolutionsAjit Narang, Ph.D., Principal Scientist, Drug Product Science and Technology, Bristol-Myers SquibbEmerging data suggests that aggregation instability of a ready-to-use protein solution drug product may be linked to the shear forces experienced by the protein during downstream purification. Sustained conformational changes due to shear during processing may contribute to long-range hydrophobic protein-protein interactions in protein solutions. These interactions manifest in changes in the physicochemical properties of proteins including viscosity and hydrodynamic diameter, in addition to protein aggregation during accelerated stability testing.

09:05 Understanding Your Molecule Using Design of Experiment ModelingJonathan Armer, Scientist I, Formulation Sciences, MedImmune Ltd.

Different strategies exist for examining specific attributes of a molecule. This data can be used to make judgements on formulation choices by weighing each of the key stability indicating attributes. Identifying the correct formulation parameters, against often conflicting data, can be challenging. The use of Design of Experiment software to analyze and model these data will be discussed. Ways to leverage these models to make long term stability predictions will also be explored.


Table 25: Approaches to and Prediction of Long Term StabilityModerator: Ernesto Freire, Ph.D., Professor, Biology and Biophysics, Johns Hopkins University

Table 26: Characterization of ADC Degradation PathwaysModerator: Janet L. Wolfe, Ph.D., President,, Wolfe Laboratories, Inc.

Table 27: High Concentration Protein Formulations – What Are The Limitations of Our Current Analytical Methods?Moderator: Thomas Hey, Ph.D., Director, Biochemistry, Innovation Center Complex Formulations, Fresenius Kabi Deutschland GmbH

Table 28: Early/Pre-formulation Strategies to Assess Developability of a New MoleculeShahid Uddin, Ph.D., Director, Formulation, MedImmune


FORMULATION CONSIDERATIONS FOR EXISTING AND EMERGING BIOMOLECULES (cont’d)

11:00 Challenges and Strategies for the Accurate Analysis of Protein Integrity in Sustained Release Depot FormulationsSyed Reza, M.D., Ph.D., Director, Business Development, Octoplus NVControlled release microspheres of therapeutic proteins present some special challenges in pharmaceutical analytical development. Microspheres contain high weight percentage of polymer which contributes to high background noise and interference by the polymer component in analysis of protein. Approaches to methods for protein content, identify, purity and bioactivity will be discussed. Extended duration microspheres present an added complexity of protein inactivation in situ. Analytical methods to assess protein integrity during the release phase shall also be presented.

11:30 Protein Conjugates with Hydroxyethylstarch - High Solubility and Low ViscosityThomas Hey, Ph.D., Director, Biochemistry, Innovation Center Complex Formulations, Fresenius Kabi Deutschland GmbHHESylation® - the attachment of the biodegradable and poorly immunogenic polymer hydroxyethyl starch (HES) to therapeutic proteins - results in an increased efficacy by stabilization of the protein and prevention of renal excretion. The resulting conjugates show high solubility, but low viscosity compared to the PEGylated protein, allowing s.c. administration also of highly concentrated solutions.

12:00 Toward Stable Formulations of Peptides: Lessons LearnedAnna-Karin Lundbeck, Ph.D., Formulation Scientist, MedImmune Ltd.Peptides are becoming an increasing popular drug target and therefor there is a demand to better understand how to successfully formulate peptides to preserve stability and efficacy over time. The physical and chemical degradation pathway of peptides can be very complex and require extensive studies to be able to predict stable formulations. In this talk I aim to elucidate some of the learnings that have been made during the course of developing a stable formulation of a peptide.


ADVANCED AND HIGH-THROUGHPUT TECHNIQUES FOR FORMULATION DEVELOPMENT

14:00 Chairperson’s RemarksLisa A. Kueltzo, Ph.D., Staff Scientist, Formulation Development, Vaccine Production Program Laboratory, National Institutes of Health


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14:05 Advanced Analysis of Kinetic Stabilities of IgGs Modified by Mutations and Solvent AdditivesErik Sedlak, Ph.D., Associate Professor, Centre for Interdisciplinary Biosciences and Department of Biochemistry, P.J. Šafárik University in KošiceThe complex thermal transitions of IgGs and their irreversibility pose a challenge to the proper determination of parameters describing their thermodynamic and kinetic stability. We present a mathematical model to study the thermal denaturation of antibodies consisting of three (one reversible and two irreversible) consecutive transitions. The parameters obtained allowed us to examine the effects of mutations and solvent additives on the stabilities of individual domains within the full-length IgG.

14:35 Protein Stabilisation and Formulation Using Semifluorinated AlkanesGesche Graf, Ph.D., Analytical Development Manager, Novaliq GmbHSemifluorinated Alkanes (SFAs) serve as a well-tolerated alternative drug delivery medium to water. The SFA platform technology allows formulating APIs as solution or dispersion which are otherwise unstable or poorly water soluble. Formulating peptides and proteins with the help of SFAs combines both, the stabilising effect of the SFAs on peptides and proteins as well as their superior physico-chemical properties for the use in fields such as ophthalmology.

15:05 Recent Advances in the Prediction of Long Term Stability of Biologics Using ICDErnesto Freire, Ph.D., Professor, Biology and Biophysics, Johns Hopkins UniversityNew developments have demonstrated that ICD (Isothermal Chemical Denaturation) is capable of identifying the predominant mode of aggregation of biologics; quantifying the fraction of the protein that is denatured or aggregated and also quantifying the total fraction of the protein that is aggregated. These can be achieved as soon as the protein solution is prepared. The predictive capability of ICD and its application to formulation optimization will be discussed.

15:35 Comparison of Isothermal and Thermal Ramping Approaches to Vaccine FormulationLisa A. Kueltzo, Ph.D., Staff Scientist, Formulation Development, Vaccine Production Program Laboratory, National Institutes of HealthThe use of isothermal methods, such as kD and ICD measurements, has gained renewed interest. This talk will examine the comparative value of accelerated temperature methods with alternate isothermal methods, specifically in the development of low concentration vaccine formulations. The benefits and disadvantages of the thermal ramping methods such as DSC and DSF techniques will be reviewed, and the relative predictive ability for real-time stability will be examined.

16:05 Development of a High-Throughput Screening Platform to Study the Adsorption of Antigens onto Aluminum-Containing AdjuvantsVanessa Jully, Ph.D. Student, Vaccine Discovery and Development, GlaxoSmithKline VaccinesWe have developed a robust, rapid, and reproducible high-throughput screening (HTS) platform to study the adsorption capacity of aluminium-containing vaccines. The adsorption isotherms on aluminum hydroxide and aluminum phosphate of two model proteins, and two vaccine antigens were evaluated using a liquid handling system, which permitted rapid sample preparation in a small volume without nonspecific adsorption. This platform should accelerate data acquisition during the development of a new vaccine.


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BIOPRODUCTION & PROTEIN PROCESSING STREAM



Recommended Short Courses*SC4: Protein Purification Strategies: Dealing with Proteins that Are Prone to Aggregate


MONDAY, 2 NOVEMBER



13:50 Streamlining Protein Expression & ProductionLorenz M. Mayr, Ph.D., Vice President & Global Head, Reagents & Assay Development, Innovative Medicines/Discovery Sciences, AstraZenecaUntil recently, protein expression has been seen as a rather mature business with well-established technologies and highly standardized processes for the production of recombinant proteins. Due to significant technological advancements in the field of transient gene expression (TGE), we need to change our perception. The field of mammalian transient gene expression has now started to become one of the most dynamic areas of modern

biotechnology with a steady flow of novel technologies and product innovations for the enhanced production of recombinant proteins in their native physiological environment, performed with high success rates and high yields.Lorenz Mayr will discuss the comprehensive and contemporary activities for transient gene expression at AstraZeneca. He will describe new developments around these technologies for the generation of high-performance protein expression systems.

14:30 Mechanically Refolding Proteins beyond Unboiling an EggGregory A. Weiss, Ph.D., Professor of Chemistry, Molecular Biology and Biochemistry, University of California, IrvineTraditionally, refolding proteins involves arduously optimising conditions to coax protein solution into thermodynamic equilibrium. Using a Vortex Fluid Device, my lab has applied shear stress during refolding to overcome barriers between protein folding states, rapidly driving refolding. For processes not dialysis-dependent, this accelerated refolding allows a more thorough search for conditions favoring protein stability. We have demonstrated VFD-based protein refolding on

recombinant proteins, plus refolded lysozyme from boiled egg whites.





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PURIFYING ANTIBODIES

16:30 Chairperson’s RemarksDirk Linke, Ph.D., Professor, Molecular Microbiology, Biosciences, University of Oslo

16:35 Magnetically-Driven Hybrid Technologies for Antibody PurificationAna Cecília Afonos Roque, Ph.D., Assistant Professor, Chemistry, UCIBIO, Faculdade de Ciências e Tecnologia, Universidade Nova de LisboaTwo magnetically-driven hybrid technologies have been recently proposed by our group as novel alternatives for non-chromatographic antibody purification. One approach concerns with the incorporation of magnetic particles into macroporous structures to confer a magnetic response to the new composites. This magnetic response was explored for accelerated and efficient protein elution. In a second approach, the potential to combine aqueous two-phase extraction with magnetic separation was explored with success.

17:05 Purification of Common-Light-Chain Bispecific AntibodiesJuergen Nett, Ph.D., Associate Director, High Throughput Expression, Adimab LLCA variety of bispecific constructs benefit from the use of a single variable light region pairing with multiple distinct variable heavy regions. This talk will demonstrate new techniques to purify these common-light-chain bispecific IgG molecules to homogeneity. A panel of bispecific constructs are then generated that bind to each target with high affinity and exhibit favorable biophysical properties similar to traditional therapeutic antibodies.

17:35 Aqueous Two-Phase Systems: A New Platform for Antibody PurificationMaria Raquel Aires-Barros, Ph.D., Full Professor, Institute for Bioengineering and Biosciences, Bioengineering Department, Instituto Superior Técnico, Universidade de LisboaAqueous two-phase systems (ATPS) have proven to be a valuable option for the downstream processing of monoclonal antibodies (mAbs), combining a high biocompatibility and selectivity with an easy and reliable scale up and capability of continuous operation. A continuous process based in ATPS was developed by our group, for the capture of mAbs from mammalian cell culture supernatants. Furthermore, an ATPS microfluidic platform was designed as an effective tool to accelerate bioprocess design and optimization.’’



TUESDAY, 3 NOVEMBER


PURIFYING MEMBRANE PROTEINS

08:30 Chairperson’s RemarksKarin Felderer, Ph.D., Associate Director, Protein Production, Protein Sciences, MorphoSys AG

08:40 Bacterial Membrane Separation, Fractionation and Solubilization as Essential Steps in Membrane Protein PurificationDirk Linke, Ph.D., Professor, Molecular Microbiology, Biosciences, University of OsloWe strive to compare and improve different protocols for the fractionation of proteins from Gram-negative bacteria into outer membrane, cytoplasmic membrane, periplasmic, and cytosolic fractions. I will compare 5 methods for membrane fractionation, and will discuss downstream processing and protein purification. I will also show recent data on fluorescence labeling of different membrane systems, that we use to track yield and purity of our membrane samples.

09:10 GPCR Structural Biology: A Case Study with a Novel Fluorescent Fusion PartnerSaurabh Sen, Ph.D., Principal Scientist, Immune Modulation and NBE Discovery, Boehringer Ingelheim Pharmaceuticals, Inc.Structural biology of membrane proteins and GPCRs has seen major advances over the past few years, but overcoming the challenges of functional GPCR expression and structural stabilization are still time-consuming and expensive. The talk will focus on an approach that combines a powerful cloning strategy with novel transmembrane guides and a novel fluorescent reporter which significantly increases functional receptor expression in E. coli along with other downstream processing benefits.


Table 7: Bottlenecks in the Purification of BiotherapeuticsModerator: David O’Connell, Ph.D., Lecturer & Director, MSc Programmes in Biotherapeutics, Biomolecular & Biomedical Research, University College Dublin

Table 8: Systems for GPCR Expression: Have We Identified the Best Yet?Moderator: Saurabh Sen, Ph.D., Principal Scientist, Immune Modulation and NBE Discovery, Boehringer Ingelheim Pharmaceuticals, Inc.

Table 9: Transition of Projects from Discovery to Development: What are Important Points to Consider or Lessons Learned?Moderator: Stefan Schmidt, Ph.D., Vice President, Process Science & Production, Rentschler Biotechnologie GmbH



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AFFINITY PURIFICATION11:20 Recombinant Production and Utilization of Affinity of ProteinsSophia Hober, Ph.D., Professor, Protein Technology, Biotechnology, KTH Royal Institute of TechnologyStrategies for optimization of protein production and purification will be presented as well as a miniaturized high throughput method for protein verification. Fusion tags for improved selectivity of protein purification processes including protein domains with dual affinity will be presented. The dual affinity design can be of advantage for protein purification as well as other applications where affinity to more than one target molecule can be of value. Moreover, a novel, affinity-based method, that renders site-specific labeling of antibodies possible will be discussed.

11:50 Application of a Novel Fragment Complementation-Based Affinity System for Improved Protein Purification in a Single Step – from Highly Soluble to Membrane Proteins and Therapeutic Binder MoleculesDavid O’ Connell, Ph.D., Lecturer & Director, MSc Programmes in Biotherapeutics, Biomolecular & Biomedical Research, University College DublinIn this presentation the performance of a novel EF hand-based fragment complementation system will be highlighted for the purification of GFP, carbonic anhydrase, GPCR and DARPin binder proteins. The application of a single-step purification rationale will be compared to tandem affinity purification approaches and downstream assays will be described.


13:20 Session Break


OVERCOMING PURIFICATION CHALLENGES

14:30 Chairperson’s RemarksDavid O’ Connell, Ph.D., Lecturer & Director, MSc Programmes in Biotherapeutics, Biomolecular & Biomedical Research, University College Dublin

14:35 Case Studies: IDPs “Intrinsically Disordered Proteins,” Difficult to Produce, but with a Significant Role in Cellular PathwaysMario Lebendiker, Ph.D., Head, Protein Purification Facility, Wolfson Centre for Applied Structural Biology, Institute of Chemistry, The Hebrew University of JerusalemDisordered domains in IDPs “Intrinsically disordered proteins” or IDRs “Intrinsically disordered regions” play a significant role in cellular pathways, with an enormous potential as medical targets. Because of their lack of stable tertiary structure and their dynamic interchanging extended and flexible conformations, these types of proteins are prone to aggregate, and constitute an extraordinary challenge to produce. We’ll briefly illustrate here our strategy to produce enough amounts of these type of targets for biophysical and biochemical studies that allows us to show the way by which such domains act.

15:05 High Yield Expression of Protein Kinases in Insect CellsSvend Kjaer, Ph.D., Head, Protein Purification, Structural Biology Science Technology Platform, Francis Crick InstituteBaculovirus mediated infection of insect cells is a well-established technology for production of proteins with many end-point applications. In this presentation, I’ll present data on the expression and purification of a kinase target and demonstrate the importance of co-expression strategies for downstream success. Moreover, data on a generic method, which significantly improves yields by infection of insect cell at high cell densities will be presented.

15:35 How to Get the High Hanging Fruits – Tools for Generation of Difficult-to-Express AntigensKarin Felderer, Ph.D., Associate Director, Protein Production, Protein Sciences, MorphoSys AGA critical but often unaccounted factor in successful discovery and development of therapeutic antibodies is the availability of high quality antigens and tool proteins in sufficient amounts. The presentation will focus on the development of a novel lysozyme-based expression/purification tag system allowing us to produce difficult-to-express proteins of high quality as soluble monomers. Diverse case studies on expression of human CD19, Fc receptors and other proteins will be presented.

16:05 Native and Stabilized Membrane Proteins for Sponsored by Drug DiscoveryAnass Jawhari, Ph.D., CSO, CALIXARCALIXAR has developed patented technology based on new chemistry approach to safely isolate membrane proteins (GPCR, ion channels, transporters, enzymes and viral proteins) for drug discovery (antibody development, ligand screening, SBDD and vaccine application). The presentation will illustrate some case studies including Adenosine receptor A2A that was solubilized and purified without any single mutation, truncation or fusion for antibody development purposes and crystallization.


INNOVATING PURIFICATION PROCESSES

17:15 Robust Design of Continuous Purification of Adenovirus Vectors by Two-Column, Simulated Moving-Bed, Size-Exclusion ChromatographyJosé Paulo Mota, Ph.D., Professor, Chemical and Biochemical Engineering, Animal Cell Technology, iBET & FCT-Universidade Nova de LisboaA two-column simulated moving-bed (2CSMB) process for continuous purification of adenoviral vectors by size-exclusion chromatography is presented and validated experimentally, and a general procedure for its robust design under parameter uncertainty is described. The pilot-scale runs yield a virus recovery of 86% and impurity clearance of 90% without any fine-tuning of the operating parameters. This yield is 60% better and the productivity is increased by 6-fold with respect to single-column batch chromatography for the same volume of resin.


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17:45 Estimating Protein Phase Behavior Based on Osmotic Virial Coefficients – A Thermodynamics-Based ApproachChristian Kress, Dipl.-Ing, Scientist, Biochemical and Chemical Engineering, Laboratory of Thermodynamics, Technical University of BerlinCurrently product capturing within protein production is often based on Protein-A chromatography, limited in capacity and scalability, which leads to a demand for different workup strategies (e.g. extraction by ATPS or precipitation). In order to enable estimations on the applicability of these workup strategies, models to calculate partition coefficients or protein solubility are required. Therefore a new estimation strategy based on the second osmotic virial coefficients B22 and B23 is used.

18:15 Purification of Therapeutic Proteins under Cost ConstraintsStefan Schmidt, Ph.D., Vice President, Process Science & Production, Rentschler Biotechnologie GmbHBiologicals and biosimilars represent the fastest growing segment in the drug pipeline. This puts a lot of pressure on economical manufacturing, primarily solving efficiency issues in downstream processing. Here I demonstrate how to solve challenges by applying disposables, using modular concepts, replacing costly affinity resins and reducing the number of steps in platform processes. The case studies with examples from various molecule classes highlight successful process design, optimization strategies and critical manufacturing parameters.

18:45 End of Protein Purification Technologies


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Bioreactor Design & EngineeringFinesse and Control of BioprocessesWEDNESDAY, 4 NOVEMBER


NEXT-GENERATION BIOREACTOR STRATEGIES

08:45 Chairperson’s Opening RemarksTrevor Deeks, Ph.D., QA and QC Consultant, Teva Biopharmaceuticals USA, Inc.

»KEYNOTE PRESENTATION8:50 How Can Measurement, Monitoring, Modeling and Control Advance Animal Cell Culture in Industrial Biotechnology?

Paula Alves, Ph.D., CEO and Head, Animal Cell Technology, ITQB-UNL, Instituto de Biologia Experimental e Tecnológica (IBET)Due to its inherent biological complexity, continued success of animal cell culture makes the development of measurement, monitoring,

modeling and control methodologies critical both in academic and industrial environments. Examples of prominent developments include methods for omic data generation and glycoprotein characterization, tools for real-time monitoring of cell culture performance, and hybrid modeling approaches to extract process understanding. This talk will address different cell types and products, identifying challenges for bioprocess optimization while meeting product quality attributes.

09:35 Large-Scale Production of Phage Antibody Libraries Using a BioreactorAndrew Bradbury, MB, BS, Ph.D., Group Leader and Research Scientist, B Division, Los Alamos National LaboratoryOne limitation of high-throughput phage antibody library selections is the production of sufficient phage antibody library at the appropriate quality. This talk will describe the adaptation of a bioreactor-based protocol for the production of phage peptide libraries to the production of phage antibody libraries. Titers obtained in the stirred-tank bioreactor are higher than a standard shake flask procedure, and phage antibody library quality is indistinguishable to that produced using standard procedures.

10:15 The Bolt-On Bioreactor Project - Perfusion Bioreactor Design for Efficient Adherent Cell CultureMarcos Simón, Ph.D., Founder, Bolt-on Bioreactor ProjectEfficiency of bioreactors for the culture of adherent cells lags behind that of their suspension cells counterparts. The Bolt-on Bioreactor project has studied each of the four major challenges that preclude adherent cells from becoming the biopharmaceuticals production system of choice in industry. The result is an efficient and scalable system for the perfusion culture of adherent cells.


11:30 Miniature Bioreactor Technologies for Rapid Cell Culture Process DevelopmentFrank Baganz, Ph.D., Senior Lecturer, Biochemical Engineering, University College LondonThe need for greater speed during bioprocess development has focused much attention onto the development and application of miniaturised and high-throughput devices. This presentation will focus on shaken microwell-based systems and miniature stirred tank reactors and will cover the engineering characterisation in terms of power input, liquid phase mixing, and oxygen mass transfer. Examples will be given for the application of these technologies to rationally scale-up/down cell culture processes.

12:00 Bioengineering Strategies for ex vivo Cultivation and Purification of Stem CellsJoaquim M.S. Cabral, Ph.D., Professor and Head, Bioengineering, Instituto Superior Técnico, University of LisbonThe development of reliable in vitro systems for stem cell growth is a valuable tool to study the mechanisms controlling the expansion and differentiation of stem cells. This lecture presents bioprocess concepts towards the ex vivo expansion of adult mesenchymal and pluripotent stem cells in bioreactors, while maintaining their functional characteristics, including the ability to differentiate into appropriate tissues. Additionally, recent developments are also described and discussed.


13:30 Session Break

DISPOSABLE BIOREACTORS

14:00 Chairperson’s RemarksAndrew Bradbury, MB, BS, Ph.D., Group Leader and Research Scientist, B Division, Los Alamos National Laboratory

14:05 Single-Use versus Stainless Steel Bioreactors - Quality Factors for Consideration When Selecting a Suitable SystemTrevor Deeks, Ph.D., QA and QC Consultant, Teva Biopharmaceuticals USA, Inc.The relative merits of single-use as compared to stainless steel bioreactors has been widely covered in the literature and in conference presentations. Relative cost, convenience and capabilities have been the main areas for discussion, but there has been relatively little debate about quality considerations. Quality considerations are not often part of the decision-making process to determine the type of system to select. This presentation discusses these quality factors and how they might influence the decision.


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Bioreactor Design & EngineeringFinesse and Control of Bioprocesses

14:35 Extractables from Single-Use Bioreactors and Impact on Cell Culture PerformanceYasser Nashed-Samuel, Ph.D., Principal Scientist, Attribute Sciences, Process Development, Amgen, Inc.Biopharmaceuticals are drugs manufactured by growing genetically engineered cells in bioreactors to produce a therapeutic protein. Plastic single-use bioreactors are of interest to biopharmaceutical drug manufacturers due to its significant environmental and cost benefits and flexibility over stainless steel bioreactors. Effect of plastics on the bio-manufacturing process is not yet completely understood. A case study on extractables from single-use bioreactors and impact on cell culture performance will be presented.

15:05 Scaled-Up Manufacturing of Recombinant Antibodies Produced by Plant or Animal Cells in a 200-L Orbitally Shaken Disposable BioreactorStefan Schillberg, Ph.D., Head, Molecular Biology, Plant Biotechnology, Fraunhofer Institute for Molecular BiologyThe cultivation of suspended cells in disposable bioreactors for production of recombinant proteins is a useful alternative to conventional stainless steel stirred-tank reactors, and orbitally shaken bioreactors could provide further advantages such as simple bag geometry, scalability and predictable process settings. We carried out a scale-up study, using a 200-L orbitally shaken bioreactor holding disposable bags, and plant or animal cells producing human monoclonal antibodies. Antibodies secreted to the culture medium were purified by affinity chromatography resulting in high recovery and purity.


SMALL-SCALE MODELING

16:15 Fed-Batch Operation in Small-Scale Bioreactors – Characterization of a Microtiter Plate-Based Feeding SystemClemens Lattermann, Dipl.-Ing., Scientific Staff, Biochemical Engineering, RWTH Aachen UniversityFed-batch operating conditions in small-scale screening systems are essential for an efficient bioprocess development. In this work, first an overview about recently published fed-batch screening systems is given. Furthermore, a novel shaken fed-batch microtiter plate is presented and characterized. This microtiter plate is based on substrate diffusion through a hydrogel. A simulation model has been developed, to better understand the diffusion process and the hydrogel behavior during substrate diffusion. Finally, the simulation data are compared to experimentally determined substrate release data.

16:45 Which Outputs of a CFD Simulation Really Affect Process Performance? - A Two-Step Scale-Down ApproachJens Fricke, Ph.D., Project Assistant, Bioprocess Engineering, Environmental Engineering and Technical Biosciences, Vienna University of TechnologyIn order to characterize existing processes in homogeneities in large-scale bioreactors CFD, simulations are usually performed. The questions that remain are: (1) Which of those gradients actually really affect cell physiology and thereby process performance? (2) How to anticipate those effects in small-scale in order to avoid surprises during scale-up? This contribution aims at answering those questions by proposing a link between the outputs of CFD simulations and the analysis of its physiological effects in a two-step scale-down approach.


Table 16: Are Our Processes under Control? Can We Rely on the Monitoring Systems That We Use to Provide Sufficient Information on What is Going on in the Bioreactor?Moderator: Trevor Deeks, Ph.D., QA and QC Consultant, Teva Biopharmaceuticals USA, Inc.

Table 17: Extractables/Leachables from Disposable SystemsModerator: Yasser Nashed-Samuel, Ph.D., Principal Scientist, Attribute Sciences, Process Development, Amgen, Inc.

Table 18: Are the Data We Collect on Processes Sufficiently Converted to Information? Or Do We Just Store the Data Without Really Using Them? What Can Be Improved?Moderator: Krist Gernaey, Ph.D., Professor, Chemical and Biochemical Engineering, Technical University of Denmark


19:15 End of Day


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Bioreactor Design & EngineeringFinesse and Control of Bioprocesses

THURSDAY, NOVEMBER 5


MODELING & ANALYZING PROCESSES

08:30 Chairperson’s RemarksJoaquim M.S. Cabral, Ph.D., Professor and Head, Bioengineering, Instituto Superior Técnico, University of Lisbon

08:35 Lifelines of Single Cells and Populations in Large-Scale Bioreactors – Complex Dynamic Interplay between Extracellular Environment and Cell MachineryMatthias Reuss, Ph.D., Professor & Acting Senior Director, Stuttgart Research Center Systems Biology, University of StuttgartThe purpose of strategies for the integration of computational fluid dynamics (CFD) and quantitative physiology is the development of more reliable simulation tools to accelerate the process of scale-up. The lecture aims at introducing an Euler-Lagrange approach to characterize the behavior of heterogeneous cell population in a stirred tank bioreactor with non-ideal mixing. It allows one to describe population behavior as the outcome of the interaction between the intracellular state of its individual cell and the turbulent flow field in the bioreactor.

09:05 Multivariate Analysis of Industrial Scale Fermentation DataKrist Gernaey, Ph.D., Professor, Chemical and Biochemical Engineering, Technical University of DenmarkHistorical process data is available for data mining, and can provide insight into process operation. Multivariate analysis is a powerful tool for investigating such large data sets as will be illustrated with an industrial case study. However, there are also many challenges associated with the application of multivariate analysis tools to batch process data. This is due to issues related to different batch lengths, different data sampling intervals, noise in the measurements, and availability of both online and offline data.

09:35 Rapid Intracellular Nucleoside Phosphate Monitoring in Fed Batch and Perfusion Cell Cultures using MALDI-TOF-MSRobert Steinhoff, MSc, Scientist, Chemistry and Applied Biosciences, ETH ZurichMonitoring intracellular levels of nucleoside phosphates in cell cultures allows for a very precise determination of cell viability and strongly supports process development. This interesting metabolite class is accessible using matrix-assisted-laser desorption/ionization mass spectrometry in combination with a rapid extraction protocol. The main focus of this talk is dedicated to method development steps and their application in (i) a hypothermia study in fed batch cultures and (ii) steady-state investigations in a perfusion cell culture.

10:05 Developing and Characterising a Microbioreactor for FermentationNelson Andrés Barrientos Lobos, Ph.D., Doctoral Researcher, Biochemical Engineering, University College London


INNOVATIVE APPROACHES TO ENSURE QUALITY

11:15 Orbital Shaking – The Next Generation Bioreactor System for High-Density Animal Cell Culture?Maria De Jesus, Ph.D., Co-Founder, COO and Vice President, Sciences, ExcellGene SAImpeller-free mixing of a liquid is possible. However, technical parameters of shaking processes, such as vessel geometry, direction and frequency of vessel displacement, gas transfer, power input, shear stress impact, etc. have only been explored by a few groups. For more than 10 years, we have established key engineering data and studied the culture performance of orbitally shaken cylinders from 5 ml to 50 L, to 250 L and eventually to 2500 L. This talk will cover the essentials of our research and will present surprising data of unpublished case studies with CHO cells and their performance.

11:45 Free Surface Oxygen Transfer in Unbaffled Bio-ReactorsFrancesca Scargiali, Ph.D., Assistant Professor, Dipartimento di Ingegneria Chimica, Gestionale, Informatica e Meccanica, Università degli Studi di PalermoAnimal cell damage in aerated bioreactors is mainly related to the bursting of bubbles at the air–liquid interface. A viable alternative to sparged bioreactors may be represented by uncovered unbaffled stirred tanks, which have been found to be able to provide sufficient mass transfer through the deep free surface vortex which takes place under agitation conditions so avoiding bubble formation and bursting. Mass transfer performance of this kind of bioreactor is then presented and discussed.



13:30 End of Bioreactor Design & Engineering


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http://orbit.dtu.dk/en/publications/multivariate-analysis-of-industrial-scale-fermentation-data(a481700c-5fd9-4857-b39c-877760461b94).html




Bioproduction: Scaling Up & DownModeling to Manufacturing





12:30 Registration


INNOVATING BIOPRODUCTION

13:30 Chairperson’s Opening RemarksMark Smales, Ph.D., Professor, Biotechnology, Biosciences, University of Kent

»KEYNOTE PRESENTATION13:35 Challenges and Trends Driving Innovation in Biopharmaceutical Development

Dorothee Ambrosius, Ph.D., Senior Vice President, Global Bioprocess and Pharmaceutical Development, Boehringer Ingelheim Biopharmaceuticals GmbH

»FEATURED PRESENTATION14:20 Manufacture of Therapeutic Proteins at the Point-of-CareAntonio Moreira, Ph.D., Vice Provost for Academic Affairs, Provost’s Office and Center for Advanced Sensor Technology; Professor, Chemical and Biochemical Engineering, University of MarylandOur team has been developing a compact, agile platform designed to produce therapeutic proteins at the point-of-care. In this presentation, we will describe our progress towards making a briefcase sized device that will serve as the factory of the future, and enable biologics production on-demand at the point-of-care. Our core technology uses a novel CHO cell extract for in vitro expression of virtually any protein and couples it with a simple, single step intein-based purification system that has the potential of producing a therapeutic ready for delivery to the patient.

14:50 SELECTED POSTER PRESENTATION:Optimization of 2G UNicT Technology for Enhanced Protein Production Under GS Selection in CHO-S and CHO GS -/- CellsBart Engels, Ph.D., Scientist, ProteoNic B.V.


STRATEGIES FOR ANTIBODY PRODUCTION

16:05 From Bench to GMP, Develop Quick and Clean ADC ProcessesEric LaCoste, Ph.D., ADC Team Leader, Chemistry & Biotechnology Development, Sanofi-Aventis Research & DevelopmentHow to go Quick and Clean from bench to GMP? How to deal with project constraints? The Sanofi’s ADC team develops processes in QbD-oriented strategies to rapidly deliver a scalable process contributing to process and product knowledge. Selected examples on conjugation reaction and purification development will be presented.

16:35 Bispecific Antibodies from Engineering to Optimized In-House Phase I ManufacturingStanislas Blein, Ph.D., Senior Director and Head, Antibody Engineering, Biologics Research, Glenmark Pharmaceuticals S.A.Glenmark Pharmaceutical`s BEAT® platform is a novel bispecific heavy chain hetero-dimerization platform based on a unique concept of bio-mimicry. We have produced several T cell recruiting bispecific antibodies against different cancers. Our most advanced program GBR 1302 potently re-directs T cells to HER2 positive cancer cells demonstrating strong tumour cell lysis activity with an excellent safety-efficacy window. Preclinical data and manufacturing process will be presented.

17:05 End of Day


SC8: The Challenge of Protein Aggregation and Formation of Sub Visible Particles in the Development of Biopharmaceuticals(*Separate registration required. Please see page 3 for more details.)

FRIDAY, 6 NOVEMBER


SCALING UP & DOWN

08:30 Chairperson’s RemarksAlan G. Ryder, Ph.D., Senior Lecturer, Nanoscale Biophotonics Laboratory, School of Chemistry, National University of Ireland, Galway

08:35 Scale-Down Models Enable Identification of microRNAs to Enhance Cellular Performance of Mammalian Cell FactoriesKerstin Otte, Ph.D., Professor, Molecular Biology and Gene Technology, Pharmaceutical Biotechnology, University of Applied Sciences BiberachMammalian expression systems still exhibit bottlenecks during protein production invoking efforts to improve production capacity of host cells. The development of novel engineering strategies is usually performed in small scale formats. We will present a small scale, high-throughput functional screen using microRNAs to optimize production in CHO cells revealing vast numbers of microRNAs to improve production performance. An entire miRNA family is shown to exhibit pro-productive properties transferable from small scale to larger scale formats.


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09:05 Challenges in Scale-Up of Cell Culture Processes from Lab Scale to Full CommercialChristian Sieblist, Ph.D., Manager, Science and Engineering Lab, Roche Pharma Biotech Production, Roche Diagnostics GmbH


Table 28: The Benefits and Business Case for More Standardization and Automation in BiopharmaModerator: Moritz von Stosch, Ph.D., Lecturer, Chemical Engineering and Advanced Materials, Science, Agriculture and Engineering, Newcastle University; CEO, HybPAT Technologies

Table 29: The Relevance of Integrated Bioprocess DevelopmentModerator: Jose C. Menezes, Ph.D., Professor, Bioengineering and Biosciences, Technical University of Lisbon

Table 30: Process Transfer and Manufacturing at CMOsModerator to be Announced


ENHANCING PRODUCTIVITY

11:00 Impact of Large-Scale Bioreactor Heterogeneities on Transcriptional and Metabolic Regulation in Industrial ProducersRalf Takors, Ph.D., Director, Biochemical Engineering, University of StuttgartE. coli is commonly used for recombinant protein production in lab and in production scale. When cells are exposed to large scale production conditions, they face frequently varying micro-environmental conditions due to insufficient mixing and spatial heterogeneities. This contribution shows impacts of large scale heterogeneities mirrored on the metabolic and transcriptional levels of E. coli that finally serve to optimize bioreactor design and the genomic platform of the producer cell.

11:30 CHO Cell Line Engineering – Protein Quantification on the Octet RED96Stefan Kol, Ph.D., Protein Biochemist, CHO Cell Line Engineering Core Facility, Novo Nordisk Foundation Center for Biosustainability, Technical University of DenmarkErythropoietin (EPO) quantification during cell line selection and bioreactor cultivation has traditionally been performed with ELISA or HPLC. As these techniques suffer from several drawbacks, we developed a novel EPO quantification assay. A camelid single-domain antibody fragment (VHH) directed against human EPO was evaluated as a capturing antibody in a label-free biolayer interferometry-based quantification assay. Human recombinant EPO can be specifically detected in Chinese hamster ovary cell supernatants in a sensitive and pH-dependent manner. This method enables rapid and robust quantification of EPO in a high-throughput setting.

12:00 Determination of Recombinant Mammalian Cell Line Phenotypes in the Bioreactor at the 96-Deep Well Plate Scale during Cell Line Development Using Intact MALDI-ToF Mass Spectrometry and PLS-DA ModelingMark Smales, Ph.D., Professor, Biotechnology, Biosciences, University of KentHere we described the application of an intact cell MALDI-ToF mass spectrometry fingerprinting method coupled with mathematical modeling to the cell line construction process for the prediction and isolation of high producing cell lines. We show how MALDI-ToF mass spectrometry data of cell lines gathered at the 96 deep well plate stage of cell line construction can be used to predict the phenotype of mammalian cell lines at the 10 L fermenter scale using a Partial Least Squares Discriminant Analysis (PLS-DA) model. The modeling approach provides the basis for the early prediction of cell line performance in cGMP manufacturing-scale bioreactors. We will discuss the possibility of extending the application to product quality attributes.


SINGLE-USE, MONITORING QUALITY & PROCESS EXCELLENCE STRATEGIES

14:00 Chairperson’s RemarksRavinder Bhatia, MSc, Scientific Director, PDMS/API-LM, Janssen Research & Development

14:05 Case Study: Scale-Up of an Allogeneic Cell Therapy Product Using Single-Use SystemsRavinder Bhatia, MSc, Scientific Director, PDMS/API-LM, Janssen Research & DevelopmentOne of the major challenges with cell therapy products is the development of a robust and scalable process to produce the product for clinical trials and commercialization. Currently, numerous technologies are available for the scale-up of an allogeneic cell therapy product in static (e.g. T-flasks and cell factories) or suspension (e.g. microcarriers, bioreactor type) cultures. In this presentation, a case study will be presented on process development and scale-up of an allogeneic human somatic cell therapy product using single-use technologies.

14:35 Combining Multi-Dimensional Fluorescence Spectroscopy and Chemometric Analysis for Quantitative Bioprocess MonitoringAlan G. Ryder, Ph.D., Senior Lecturer, Nanoscale Biophotonics Laboratory, School of Chemistry, National University of Ireland, GalwayMulti-dimensional fluorescence spectroscopy (MDFS) was used for quantitative predictive analysis of glycoprotein production and content in CHO cell fed-batch process. MDFS spectra of complex solutions were sensitive to compositional change and as cultivation progressed, amino acid, and glycoprotein product emission varied as the chemical composition changed and culture progress could be monitored quantitatively using a variety of multivariate analysis techniques. In one case, unique dityrosine emission from product glycoprotein could be used to follow product formation. The MDFS variance could also be used to generate quantitative predictive models of process performance based on glycoprotein yield.


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15:05 Using Different QbD Tools to Support Scale-Down and Scale-Up of Bioprocesses: Examples from Small and Large MoleculesJose C. Menezes, Ph.D., Professor, Bioengineering and Biosciences, Technical University of LisbonThe use of disciplines from the QbD (Quality by Design) tool box will be demonstrated to support science-based bioprocess industrialization and manufacturing (e.g., design-spaces, multivariate end-point and batch trajectory control). Scale-up with PAT tools and/or validated scale-down models for DoE and troubleshooting will be highlighted for small and large molecules. Process performance and product quality will be considered in these approaches.

15:35 Monoliths as PAT Tools for Bioprocess ImprovementOliver Spadiut, Ph.D., Group Leader, Integrated Bioprocess Development, Biochemical Engineering, Vienna University of TechnologyMonolithic columns are a special type of chromatography column which can be used for the purification of different biomolecules. They have become popular due to their high mass transfer properties and short purification times. However, they also describe powerful PAT tools for bioprocess monitoring and development. I will show how monoliths can be used as efficient impurity monitoring tools during bioreactor cultivations but also across unit operations for recombinant protein production processes with yeast.

16:05 Hybrid Modeling as a QbD Tool for PAT in BiopharmaMoritz von Stosch, Ph.D., Lecturer, Chemical Engineering and Advanced Materials, Science, Agriculture and Engineering, Newcastle University; CEO, HybPAT TechnologiesProcess understanding is at the heart of the PAT initiative and QbD paradigm. The integration of Risk Analysis, Design of Experiments and Multivariate Data Analysis (MVDA) is the predominantly applied approach in biopharma to understand processes, nowadays. In this talk, it will be shown that the integration of fundamental process knowledge along with MVDA into hybrid models has the potential to improve the prediction performance, reduce the experimental effort and support the knowledge exchange between scales.



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PROTEIN EXPRESSION STREAM

2-3 November 2015 | EIGHTH ANNUAL

Engineering Expression SystemsGenes, Codons, Vectors and Clones

MONDAY, 2 NOVEMBER



SC3: CHO Cell Engineering

SC4: Protein Purification Strategies: Dealing with Proteins that Are Prone to Aggregate(*Separate registration required. Please see Page 3 for more details.)


13:50 Streamlining Protein Expression & ProductionLorenz M. Mayr, Ph.D., Vice President & Global Head, Reagents & Assay Development, Innovative Medicines/Discovery Sciences, AstraZenecaUntil recently, protein expression has been seen as a rather mature business with well-established technologies and highly standardized processes for the production of recombinant proteins. Due to significant technological advancements in the field of transient gene expression (TGE), we need to change our perception. The field of mammalian transient gene expression has now started to become one of the most dynamic areas of modern biotechnology with a

steady flow of novel technologies and product innovations for the enhanced production of recombinant proteins in their native physiological environment, performed with high success rates and high yields. Lorenz Mayr will discuss the comprehensive and contemporary activities for transient gene expression at AstraZeneca. He will describe new developments around these technologies for the generation of high-performance protein expression systems.

14:30 Mechanically Refolding Proteins beyond Unboiling an EggGregory A. Weiss, Ph.D., Professor of Chemistry, Molecular Biology and Biochemistry, University of California, IrvineTraditionally, refolding proteins involves arduously optimising conditions to coax protein solution into thermodynamic equilibrium. Using a Vortex Fluid Device, my lab has applied shear stress during refolding to overcome barriers between protein folding states, rapidly driving refolding. For processes not dialysis-dependent, this accelerated refolding allows a more thorough search for conditions favoring protein stability. We have demonstrated VFD-based protein refolding on recombinant

proteins, plus refolded lysozyme from boiled egg whites.





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Engineering Expression SystemsGenes, Codons, Vectors and Clones15:50 Refreshment Break in the Exhibit Hall with Poster Viewing

VECTOR ENGINEERING

16:30 Chairperson’s RemarksKirill Alexandrov, Ph.D., Professor, Institute for Molecular Bioscience, Australian Institute of Bioengineering and Nanotechnology, University of Queensland

16:35 A Synthetic Optimised Vector System for Chlamydomonas reinhardtiiKyle J. Lauersen, Ph.D., Faculty of Biology, Algae Biotechnology & Bioenergy, Center for Biotechnology, Bielefeld UniversityMicroalgae are interesting hosts for numerous natural products and hold the capacity for light-driven photo-bioproduction. However, complicated genetics and limited molecular tools have hindered significant development in transgenic algal technologies that could further their biotechnological potential. This work presents the development of a modular versatile vector for the model microalgae Chlamydomonas reinhardtii. This system serves as a standardised platform for future genetic engineering of this valuable algal species.

17:05 In vitro Reconstitution and Analysis of Protein Interaction NetworksKirill Alexandrov, Ph.D., Professor, Institute for Molecular Bioscience, Australian Institute of Bioengineering and Nanotechnology, University of QueenslandThe exponential increase sequenced genomes has focused attention on how best to produce, study and modify the encoded gene products. We created a suite of in vitro expression Gateway vectors that allow us to rapidly express genes from human ORFeome libraries in Leishmania tarentolae cell-free system. We combine single molecule fluorescence spectroscopy and Amplified Luminescent Proximity Homogeneous Assay Screen to analyse the interactions of subunits of several in vitro reconstituted multisubunit eukaryotic protein complexes.

17:35 An Efficient Plant Virus Vector Able to Target Proteins to Different Subcellular Compartments in PlantsEszter Majer, Research Scientist, Plant Virus Biotechnology Research Group, Instituto de Biología Molecular y Celular de Plantas, CSIC-Universidad Politécnica de Valencia A plant virus-based expression system derived from tobacco etch virus (TEV; genus Potyvirus) permits the co-expression of several recombinant proteins from the same viral backbone in tobacco. In a recent work, protein targeting to chloroplasts, nuclei and mitochondria was successfully achieved from the amino terminus of the viral polyprotein and simultaneous expression of several proteins targeted to distinct subcellular locations was also demonstrated. The TEV-based system is highly promising for manipulation of plant endogenous metabolic pathways through expression of regulatory transcription factors and biosynthetic enzymes.



TUESDAY, 3 NOVEMBER


GENE ENGINEERING08:30 Chairperson’s RemarksHelene Faustrup Kildegaard, Ph.D., Co-Principal Investigator, Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark

08:40 Tailoring CHO Cell Metabolism via MicroRNA Manipulation to Boost Recombinant Protein ProductivityNiall Barron, Ph.D., Program Leader, Mammalian Cell Engineering, National Institute for Cellular Biotechnology, Dublin City UniversityMicroRNA engineering has already proved successful in enhancing various CHO cell phenotypes relevant to production of recombinant products. miR-23 has previously been demonstrated to play a role in glutamate metabolism providing an alternative source of critical metabolites for the TCA cycle, ultimately strengthening oxidative metabolism. We consider how reprogramming cellular bioenergetics through miR-23 may allow mammalian production cells to be more productive by favouring metabolic channeling into oxidative metabolism.

09:10 Bicistronic mRNAs to Enhance Membrane Protein OverexpressionJacopo Marino, Ph.D., Research Scientist, Chemistry and Biochemistry, Gene Center, University of MunichWe present an approach for improving the functional overexpression of membrane proteins in Escherichia coli using transcriptional fusions. The method involves the use of a small additional RNA sequence upstream to the RNA sequence of the target membrane protein and results in the production of a bicistronic mRNA. Transcriptional fusions do not require protease treatment and subsequent removal of the fusion protein.


Table 10: Advantages and Limitations of Cell-Free Expression Systems Moderator: Kirill Alexandrov, Ph.D., Professor, Institute for Molecular Bioscience, Australian Institute of Bioengineering and Nanotechnology, University of Queensland

Table 11: CRISPR/Cas9-Mediated Cell Factory Engineering: Opportunities and ChallengesModerator: Helene Faustrup Kildegaard, Ph.D., Co-Principal Investigator, Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark

Table 12: Integrative Approaches for Improving Heterologous Membrane Protein Expression in E. coliModerator: Jacopo Marino, Ph.D., Research Scientist, Chemistry and Biochemistry, Gene Center, University of Munich



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GENE ENGINEERING (CONT’D)

11:20 Improved CHO Cell Factories Using CRISPR Cas9 Genome Editing TechnologiesHelene Faustrup Kildegaard, Ph.D., Co-Principal Investigator, Novo Nordisk Foundation Center for Biosustainability, Technical University of DenmarkThe high efficiency of the CRISPR Cas9 genome editing technology has enabled fast and easy construction of engineered cell lines. Here, our efforts on generating precise gene disruptions and gene insertions using CRISPR Cas9 will be presented together with a fast and high-throughput platform for constructing CRISPR Cas9 reagents. In addition, examples of improved CHO cell factories generated using these technologies will be presented.

11:50 Inactivation of GDP-Fucose Transporter Gene (Slc35c1) in CHO Cells by ZFNs, TALENs and CRISPR-Cas9 for the Production of Fucose-Free AntibodiesZhiwei Song, Ph.D., Principal Scientist, Lead PI for GlycoSing Programme, Bioprocessing Technology Institute, A*STARGDP-fucose transporter gene (Slc35c1) in CHO-K1 cells was inactivated by ZFNs, TALENs and CRISPRs for the production of fucose-free antibodies. The Slc35c1 gene was also inactivated in a pre-existing antibody-producing CHO line that produces the anti-Her2 antibody. Inactivation of the GDP-fucose transporter did not affect cell growth or antibody productivity.



ENGINEERING HIGHER EXPRESSION

14:30 Chairperson’s RemarksDiethard Mattanovich, Ph.D., Professor, Microbial Cell Design, University of Natural Resources and Life Sciences, Vienna and Director, Area Systems Biotechnology and Microbial Cell Engineering, Austrian Centre of Biotechnology

»FEATURED PRESENTATION14:35 Streamlining the Expression Screening of Membrane ProteinsRay Owens, Ph.D., Head, Oxford Protein Production Facility-UK, Research Complex at Harwell and Professor, Molecular Biology, University of OxfordThe production of recombinant membrane proteins for structural and functional studies remains technically challenging due to low levels of expression and the inherent instability of many membrane proteins once solubilised in detergents. One approach to overcoming these issues is to evaluate multiple membrane protein/variants. Combining ligation independent cloning of membrane proteins as GFP fusions with expression detected by GFP fluorescence enables this to be carried out rapidly and efficiently.

15:05 Tiny but Mighty – Functional High-Content MicroRNA Screening Provides a Versatile Toolbox for Next-Generation CHO Cell EngineeringSimon Fischer, Ph.D., Scientist, BP Process Development Germany, Boehringer Ingelheim Pharma GmbH & Co. KGMicroRNAs constitute an important class of non-coding RNAs in mammals. Individual miRNAs control entire cellular pathways without adding translational burden to cells and thus have received growing attention in biotechnology. A functional high-content miRNA screening in CHO cells discovered hundreds of miRNAs to substantially improve bioprocess relevant cell functions. Our comprehensive miRNA research led to the generation of a “miRNA target catalog” providing an avenue for next-generation CHO cell engineering.

15:35 Construct Engineering Provides a Platform for High-Quality GPCR GenerationOliver Schlenker, Ph.D., Senior Research Scientist, Protein Engineering, Heptares TherapeuticsProtein engineering allows achieving high-quality protein from difficult-to-tackle G protein-coupled receptors (GPCRs). Our stabilised receptors (StaRs) enable us to express and purify material suitable for biophysical characterisation. Optimisation of protein termini and utilisation of fusion proteins result in significant improvements in expression, quality and crystallisation. We provide a powerful solution for high-end quality protein delivery to find drug candidates for diseases such as Alzheimer’s and diabetes.

16:05 Superior Protein Yields in CHO and HEK-293 Cells Sponsored by Using a Novel, Highly Efficient Transfection Reagent - FectoPRO®Jelena Vjetrovic, Ph.D., Bioproduction Technical Support Specialist, Polyplus-transfection, FranceLow transfection efficiency of CHO cells is a major bottleneck hampering Transient Gene Expression (TGE). Polyplus-transfection®, with its 10+ year expertise in transfection, has developed a novel technologically advanced transfection solution specifically designed for bioproduction. FectoPRO® outperforms currently available PEI-based and lipid-based transfection reagents in both CHO and HEK-293 cells in variety of commercially-available media. We will present data and protocols leading to unmatched protein and antibody yields in CHO and HEK-293 cells as well as customer data that substantiate our findings.


ENGINEERING HIGHER EXPRESSION (CONT’D)17:15 Metabolic Engineering of NADPH Supply Enhances Recombinant Protein Production in Pichia pastorisDiethard Mattanovich, Ph.D., Professor, Microbial Cell Design, University of Natural Resources and Life Sciences, Vienna and Director, Area Systems Biotechnology and Microbial Cell Engineering, Austrian Centre of BiotechnologyBased on a genome-scale metabolic model of the yeast Pichia pastoris we predicted gene knockouts and gene overexpressions in the central metabolism to improve recombinant protein production. Experimental validation showed that the best effect was achieved by enhancing the pentose phosphate pathway, which is the major supplier of reduced NADPH. The optimum metabolic interventions will be discussed based on detailed analysis of gene regulation and metabolic fluxes.


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17:45 Enhanced Protein Production by Transient Transfection of HEK293 by Extended Gene ExpressionFrancesc Gòdia, Ph.D., Professor, Chemical Engineering, Universitat Autònoma de BarcelonaExtended gene expression (EGE) is a strategy proposed to prolong the production period of recombinant proteins by HEK293 cells transient transfection by repeatedly transecting cell cultures, together with performing a medium exchange. The benefits of this method are discussed for the production of three model products including two recombinant proteins (intracellular and secreted GFP) and a complex VLP (Gag-based VLPs).

18:15 INTERACTIVE PANEL DISCUSSION: Enabling Protein Expression through Intelligently Engineered PlatformsTechnical challenges for accelerating recombinant protein production persist from genes to vectors to constructs to clones, and these multiple variables are required when developing reliable expression systems. This panel gathers experts to debate the benefits and tradeoffs of traditional and novel engineering strategies that lead to greater, faster high-quality biotherapeutics.Moderator: Diethard Mattanovich, Ph.D., Professor, Microbial Cell Design, University of Natural Resources and Life Sciences, Vienna and Director, Area Systems Biotechnology and Microbial Cell Engineering, Austrian Centre of BiotechnologyPanelists:Niall Barron, Ph.D., Program Leader, Mammalian Cell Engineering, National Institute for Cellular Biotechnology, Dublin City UniversitySimon Fischer, Ph.D., Scientist, BP Process Development Germany, Boehringer Ingelheim Pharma GmbH & Co. KGFrancesc Gòdia, Ph.D., Professor, Chemical Engineering, Universitat Autònoma de BarcelonaRay Owens, Ph.D., Head, Oxford Protein Production Facility-UK, Research Complex at Harwell and Professor, Molecular Biology, University of OxfordOliver Schlenker, Ph.D., Senior Research Scientist, Protein Engineering, Heptares Therapeutics

18:45 End of Engineering Expression Systems


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Applying Expression PlatformsMeeting the Demand for Recombinant Proteins


SC3: CHO Cell Engineering

SC4: Protein Purification Strategies: Dealing with Proteins that Are Prone to Aggregate




CELL LINE DEVELOPMENT

08:30 Chairperson’s Opening RemarksZhiwei Song, Ph.D., Principal Scientist, Lead PI for GlycoSing Programme, Bioprocessing Technology Institute, A*STAR

»KEYNOTE PRESENTATION08:35 Alternative Cell Line Development: The Use of Polycistronic Vectors and Alternate-Splicing for Multimeric Protein Expression

Pierre Moretti, Ph.D., Head, Cell Line Development, Glenmark PharmaceuticalsThis talk introduces the alternate splicing-based multicistronic vectors developed at Glenmark for the expression of multimeric protein such

as bispecific antibodies.

09:20 Boosting Antibody Cell Line Performance without Compromising the Desired Glycan CompositionVolker Sandig, M.D., Ph.D., CSO, ProBioGen An optimal and consistent glycan pattern is desired for novel antibodies while reproduction of the original pattern is critical for biosimilar development. When selecting the final clone, posttranslational modifications may get in conflict with process performance and maximal titer. An advanced flexible vector platform and control of complex N-Glycans (including fucosylation, galactosylation and sialylation) with heterologous enzymes, glycan precursors and microelements support the perfect choice for each antibody.

09:50 A Quick and Efficient Method to Generate Mammalian Stable Cell Lines Based on a Novel Inducible Alphavirus DNA/RNA Layered SystemAlejandro Aranda, Ph.D., Principal Investigator, Vectors Development Lab, END-ICAP Unit, INSERM, University of Versailles – Saint Quentin en YvelinesWe report a new method to generate high-expressing mammalian cell lines in a quick and efficient way. For that purpose, we developed a master cell line (MCL) containing an inducible alphavirus vector expressing GFP integrated into the genome. New cell lines can be generated based on MCL by recombinase mediated cassette exchange, leading to quick generation of inducible cell lines expressing proteins of therapeutic interest.

10:20 Platform Expression Systems for Rapid Sponsored by Development of Microbial & Mammalian Cell Lines for Biopharmaceutical ProductionIan Hodgson, Ph.D., BSc, Head, Molecular Biology, FUJIFILM Diosynth BiotechnologiesThe process development of biopharmaceuticals demands concise timelines (to get products into clinic quickly), high product titres (with correct product quality), coupled with the ability to use the same expression system throughout the product life cycle. We have developed platform approaches to cell line development for both bacterial and mammalian expression, which combine all of these attributes. We will describe the development of these systems, and show data that demonstrates their performance.


11:30 Expression and Cell Line Development of Complex and Fc-Modified Therapeutic AntibodiesJohannes Auer, Ph.D., Principal Scientist, Large Molecule Research, Roche Pharma Research & Development, Roche Innovation Center PenzbergThe process of generating complex therapeutic antibodies from first test expressions until the selection of cell clones for the primary seed bank will be described. Exemplified insights will be presented into how we determine individual characteristics of a given molecule, how we balance quantity and quality of the product and how we deal with proof of monoclonality of cell clones and their stable productivity for clinical supply.

12:00 Generation of Tagged Mammalian Cell Lines with an Improved Recombinase Exchangeable CassetteJohannes Spehr, Ph.D., Research Scientist, Recombinant Protein Expression, Helmholtz Centre for Infection ResearchRecombinase mediated cassette exchange (RMCE) is a fast and reliable technique to stably integrate a gene-of-interest into a well-characterized master cell line. By using the trifunctional selective marker Hygromycinephosphotransferase-Thymidinkinase-eGFP (HTG) we improved and accelerated the generation of new producer cell lines for high expression. The HTG combines positive selection for Hygromycin and eGFP during master cell line generation with negative selection on Ganciclovir during cassette exchange.

12:30 Rapid Production of Recombinant Proteins Sponsored by and Stable Cell LinesPeer Heine, Ph.D., Field Application Scientist, MaxCyte, Inc.Success means getting to market fast. Therefore, fast and efficient protein production for drug candidate development, characterization, and selection is critical. Creating a stable cell line for clinic trial, takes months to more than a year for complicated proteins. High efficiency, scalable electroporation can reduce stable cell line development timelines by up to 50%, even in difficult-to-transfect cell lines. In this presentation, data will show the rapid production of proteins and cell lines at different scales.


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CONSTRUCTING HIGH PRODUCERS THROUGH GENOME ENGINEERING

14:00 Chairperson’s RemarksCecília Calado, Ph.D., Professor, Chemical Engineering Department, ISEL-Instituto Superior de Engenharia de Lisboa, Instituto Politécnico de Lisboa

14:05 Sequencing the CHO DXB11 Genome Reveals Regional Variations in Genomic Stability and HaploidyChristian Schrøder Kaas, Research Scientist, Mammalian Cell Technology, Novo Nordisk A/SThe copy number from each gene in the genome was calculated from next-generation sequencing data and revealed an unexpected degree of haploidy in Chinese Hamster Ovary (CHO) cells. The data can further be mined to reveal areas of the genome shown to be stable, such as chromosomes one and four, which can be hypothesised to host favourable landing platforms for targeted integration of transgenes encoding coagulation factors or antibodies.

14:35 Tunable Gene Expression Control of the RiboTite SystemNeil Dixon, Ph.D., MRSC, BBSRC David Phillips Research Fellow, Manchester Institute of Biotechnology, Faculty of Life Sciences, University of ManchesterHere we report the development and application a novel recombinant E. coli expression system that operates at translational level. The RiboTite system has been benchmarked against classical gene expression control mechanisms for the production of various reporter and target proteins of clinical importance. The system permits tunable cellular level regulation, tight basal control, high levels of expression upon induction, and predictable specific production rates across a range of growth temperatures.

15:05 Minimally Invasive Host Cell Design and Growth Decoupled Protein Production - New Concepts to Further Advance E. coli Expression SystemsGerald Striedner, Ph.D., Assistant Professor, Biotechnology, University of Natural Resources and Life SciencesOur E. coli expression system design is strongly focused on making them fit for production conditions. One strategy to improve fitness and performance of production cells is the reduction of the recombinant infrastructure to essential compounds to minimise metabolic load and cell response to recombinant gene expression. An alternative concept is based on decoupling cell growth and product formation to allocate cells’ full protein synthesis capacity to recombinant protein production.


CONSTRUCTING HIGH PRODUCERS THROUGH BIOPROCESS

16:15 Cell Line Development and Early Bioprocessing: An Integrated Data Management Solution to Select the Right CloneClaudia Götzberger-Schad, Ph.D., Senior Scientist, Global Biologics, Bayer Pharma AGWe present an integrated data management platform supporting the clone selection in the Cell Line Development (CLD) process. The system tracks all clones screened in high-throughput mode, collects all relevant characterisation data, such as productivity and quality parameters, and streamlines high-throughput workflows by interfacing with automation equipment and bioreactors at different scales. A special focus of the presentation will be on fermentation in small-scale bioreactors to assess quality and to guide clone selection and upscaling campaigns.

16:45 In situ Near-Infrared versus High-Throughput Mid-Infrared Spectroscopy to Monitor Biopharmaceuticals ProductionCecília Calado, Ph.D., Professor, Chemical Engineering Department, ISEL-Instituto Superior de Engenharia de Lisboa, Instituto Politécnico de LisboaGlobal regulatory agencies impose stringent quality guidelines concerning biopharmaceutical production that have been changing to meet the Quality by Design (QbD) framework. Highly sensitive analytical techniques, as the ones based on Fourier Transformed Infra-Red (FTIR) spectroscopy enabling simultaneous characterisation of heterologous product synthesis and physiologic cell behavior, are therefore desirable. We compare in situ near-FTIR versus high-throughput Mid-FTIR spectroscopy concerning monitoring of critical process variables and general cell physiology.


Table 19: Opportunities and Challenges of Bacterial Production Strain Engineering Using Synthetic BiologyModerator: Neil Dixon, Ph.D., MRSC, BBSRC David Phillips Research Fellow, Manchester Institute of Biotechnology, Faculty of Life Sciences, University of Manchester

Table 20: Protein Glycosylation: Challenges and Opportunities for the Biotech IndustryModerator: Zhiwei Song, Ph.D., Principal Scientist, Lead PI for GlycoSing Programme, Bioprocessing Technology Institute, A*STAR

Table 21: How to Shorten the Timeline for Drug Development with Large-Scale TGE in CHO Cells Moderator: Peer Heine, Field Application Scientist, MaxCyte


19:15 End of Day


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CASE STUDIES: UPSTREAM DECISIONS LEAD TO DOWNSTREAM SUCCESSES

08:30 Chairperson’s RemarksGeorg Klima, Executive Director, Process Science Austria, Biopharmaceuticals Division, Boehringer Ingelheim RCV

»FEATURED PRESENTATION08:35 From Bench to Clinic – Fast Track Process Development for Novel Biotherapeutics in Microbial Expression SystemsGeorg Klima, Executive Director, Process Science Austria, Biopharmaceuticals Division, Boehringer Ingelheim RCVNovel biotherapeutic formats pose unique development challenges as established platform processes are rarely applicable. To achieve rapid assessment of novel constructs’ safety in nonclinical and clinical testing, alternative process development strategies are required. A versatile toolbox approach utilising E. coli and Pichia pastoris expression systems and automated high-throughput process development will be presented. Further, we highlight a systematic approach for robust scale-up and transfer from bench to clinical scale manufacturing.

09:05 Eukaryotic Lysates for Cell-Free BioproductionMarlitt Stech, Ph.D., Research Scientist, Cell-Free Bioproduction, Fraunhofer Institute for Cell Therapy and Immunology (IZI), Branch Bioanalytics and Bioprocesses Potsdam-Golm (IZI-BB)We introduce novel systems for the cell-free production of glycoproteins, membrane proteins and functional antibody fragments in an endotoxin-free environment. The eukaryotic translation systems developed are based on translationally active lysates from cultured Sf21 and CHO cells which contain endogenous microsomal vesicles. The presence of these microsomes enables a co-translational translocation of target proteins, improved conditions for protein folding and enrichment and their subsequent posttranslational modification.

09:35 Modular Expression Approaches Using Transient and Stable Mammalian ProductionMark Trautwein, Ph.D., Senior Research Scientist, Cell and Protein Sciences, Bayer HealthCareSuccessful antibody lead discovery requires high-quality antigens, either as recombinant proteins or displayed on cellular surfaces. However, antigen production has notorious pitfalls in expression and purification. To ensure high probability of success while minimising resource demands and keeping short timelines, we have implemented a step-wise approach using transient and stable expressions in different mammalian host cell lines taking advantage of a modular expression toolbox allowing high-throughput expression optimisation.

10:05 cGMP Biologics Production Using Corynex® : Sponsored by A Highly-Productive Gram-Positive Microbial Protein Secretion SystemYoshimi Kikuchi, Ph.D., Principal Researcher, Ajinomoto Co., Inc.Corynex® is Ajinomoto’s highly productive protein expression system based on the gram-positive bacteria C. glutamicum. The easy-to-handle platform can secrete correctly-folded proteins directly into media with high purity, free from cell lysis, refolding, endotoxins, and spores. We recently demonstrated successful 1000L GMP biologics production using Corynex®.


CASE STUDIES: UPSTREAM DECISIONS LEAD TO DOWNSTREAM SUCCESSES (CONT’D)

11:15 The Incorporation of Non-Natural Amino Acids Enables Empowered Antibodies for Cancer TherapyGang Yin, Ph.D., Principal Scientist, Protein Biochemistry, Sutro Biopharma, Inc.A cell-free protein synthesis system was engineered for site-specific incorporation of non-natural amino acids (nnAAs). Methods have been developed for conjugation of synthetic molecules to antibodies or antibody to antibody by Azide/DBCO or Tetrazine/Trans-cyclooctenes reaction at desired sites. Incorporation of non-natural amino acids and development of conjugation chemistries enable empowered antibodies for cancer therapy. Three applications were discussed: antibody drug conjugates with single warhead and combination warheads, bispecific antibodies, and extended half-life antibodies by pegylation.

11:45 Wacker Biotech Refolding Technology – The Sponsored by Complement to our ESETEC® Secretion PlatformGuido Seidel, Ph.D., Managing Director, Operations, Wacker Biotech GmbHWacker Biotech is known as THE MICROBIOAL CMO. We lead the development of innovative, cost-saving E. coli technologies for recombinant manufacturing of biopharmaceuticals. Depending on customers need we can produce difficult to expressed proteins via E. coli Secretion Technology - ESETEC® or with our proprietary refolding technology.



13:30 End of Applying Expression Platforms


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12:30 Registration


INNOVATING BIOPRODUCTION

13:30 Chairperson’s Opening RemarksMark Smales, Ph.D., Professor, Biotechnology, Biosciences, University of Kent

»KEYNOTE PRESENTATION13:35 Challenges and Trends Driving Innovation in Biopharmaceutical Development

Dorothee Ambrosius, Ph.D., Senior Vice President, Global Bioprocess and Pharmaceutical Development, Boehringer Ingelheim Biopharmaceuticals GmbHThe world market for biopharmaceuticals is predicted to reach

~$145 billion in 2016 (Thomson Pharma for R&D pipeline, April 2015) reflecting a market share of ca. 25% and an annual growing rate of > 5%. Cost pressure by payers and healthcare organization are increasing, and also price competition due to Biosimilars will drive innovation for novel and better products / therapeutic principals to meet unmet medical needs, which are closely linked to and enabled by the availability of innovation in new production technologies. Despite the fact that mAbs are still the dominate molecule format, diversity in the biopharmaceutical research portfolio is increasing, driving improved and novel production technologies. As a consequence, Biopharmaceutical companies must continuously improve and innovate biopharmaceutical development and production platforms to remain competitive and respond effectively to future challenges while balancing the potential benefits with regulatory constraints and technology risks. The presentation will describe strategies and case studies for innovations in biopharmaceutical development and manufacturing.

»FEATURED PRESENTATION14:20 Manufacture of Therapeutic Proteins at the Point-of-CareAntonio Moreira, Ph.D., Vice Provost for Academic Affairs, Provost’s Office and Center for Advanced Sensor Technology; Professor, Chemical and Biochemical Engineering, University of MarylandOur team has been developing a compact, agile platform designed to produce therapeutic proteins at the point-of-care. In this presentation, we will describe our progress towards making a briefcase sized device that will serve as the factory of the future, and enable biologics production on-demand at the point-of-care. Our core technology uses a novel CHO cell extract for in vitro expression of virtually any protein and couples it with a simple, single step intein-based purification system that has the potential of producing a therapeutic ready for delivery to the patient.

14:50 SELECTED POSTER PRESENTATION:Optimization of 2G UNicT Technology for Enhanced Protein Production Under GS Selection in CHO-S and CHO GS -/- CellsBart Engels, Ph.D., Scientist, ProteoNic B.V.


STRATEGIES FOR ANTIBODY PRODUCTION

16:05 From Bench to GMP, Develop Quick and Clean ADC ProcessesEric LaCoste, Ph.D., ADC Team Leader, Chemistry & Biotechnology Development, Sanofi-Aventis Research & DevelopmentHow to go Quick and Clean from bench to GMP? How to deal with project constraints? The Sanofi’s ADC team develops processes in QbD-oriented strategies to rapidly deliver a scalable process contributing to process and product knowledge. Selected examples on conjugation reaction and purification development will be presented.

16:35 Bispecific Antibodies from Engineering to Optimized In-House Phase I ManufacturingStanislas Blein, Ph.D., Senior Director and Head, Antibody Engineering, Biologics Research, Glenmark Pharmaceuticals S.A.Glenmark Pharmaceutical`s BEAT® platform is a novel bispecific heavy chain hetero-dimerization platform based on a unique concept of bio-mimicry. We have produced several T cell recruiting bispecific antibodies against different cancers. Our most advanced program GBR 1302 potently re-directs T cells to HER2 positive cancer cells demonstrating strong tumour cell lysis activity with an excellent safety-efficacy window. Preclinical data and manufacturing process will be presented.

17:05 End of Day


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SC8: The Challenge of Protein Aggregation and Formation of Sub Visible Particles in the Development of Biopharmaceuticals(*Separate registration required. Please see page 3 for more details.)

FRIDAY, 6 NOVEMBER


SCALING UP & DOWN

08:30 Chairperson’s RemarksAlan G. Ryder, Ph.D., Senior Lecturer, Nanoscale Biophotonics Laboratory, School of Chemistry, National University of Ireland, Galway

08:35 Scale-Down Models Enable Identification of microRNAs to Enhance Cellular Performance of Mammalian Cell FactoriesKerstin Otte, Ph.D., Professor, Molecular Biology and Gene Technology, Pharmaceutical Biotechnology, University of Applied Sciences BiberachMammalian expression systems still exhibit bottlenecks during protein production invoking efforts to improve production capacity of host cells. The development of novel engineering strategies is usually performed in small scale formats. We will present a small scale, high-throughput functional screen using microRNAs to optimize production in CHO cells revealing vast numbers of microRNAs to improve production performance. An entire miRNA family is shown to exhibit pro-productive properties transferable from small scale to larger scale formats.

09:05 Challenges in Scale-Up of Cell Culture Processes from Lab Scale to Full CommercialChristian Sieblist, Ph.D., Manager, Science and Engineering Lab, Roche Pharma Biotech Production, Roche Diagnostics GmbH


Table 28: The Benefits and Business Case for More Standardization and Automation in BiopharmaModerator: Moritz von Stosch, Ph.D., Lecturer, Chemical Engineering and Advanced Materials, Science, Agriculture and Engineering, Newcastle University; CEO, HybPAT Technologies

Table 29: The Relevance of Integrated Bioprocess DevelopmentModerator: Jose C. Menezes, Ph.D., Professor, Bioengineering and Biosciences, Technical University of Lisbon

Table 30: Process Transfer and Manufacturing at CMOsModerator to be Announced


ENHANCING PRODUCTIVITY

11:00 Impact of Large-Scale Bioreactor Heterogeneities on Transcriptional and Metabolic Regulation in Industrial ProducersRalf Takors, Ph.D., Director, Biochemical Engineering, University of StuttgartE. coli is commonly used for recombinant protein production in lab and in production scale. When cells are exposed to large scale production conditions, they face frequently varying micro-environmental conditions due to insufficient mixing and spatial heterogeneities. This contribution shows impacts of large scale heterogeneities mirrored on the metabolic and transcriptional levels of E. coli that finally serve to optimize bioreactor design and the genomic platform of the producer cell.

11:30 CHO Cell Line Engineering – Protein Quantification on the Octet RED96Stefan Kol, Ph.D., Protein Biochemist, CHO Cell Line Engineering Core Facility, Novo Nordisk Foundation Center for Biosustainability, Technical University of DenmarkErythropoietin (EPO) quantification during cell line selection and bioreactor cultivation has traditionally been performed with ELISA or HPLC. As these techniques suffer from several drawbacks, we developed a novel EPO quantification assay. A camelid single-domain antibody fragment (VHH) directed against human EPO was evaluated as a capturing antibody in a label-free biolayer interferometry-based quantification assay. Human recombinant EPO can be specifically detected in Chinese hamster ovary cell supernatants in a sensitive and pH-dependent manner. This method enables rapid and robust quantification of EPO in a high-throughput setting.

12:00 Determination of Recombinant Mammalian Cell Line Phenotypes in the Bioreactor at the 96-Deep Well Plate Scale during Cell Line Development Using Intact MALDI-ToF Mass Spectrometry and PLS-DA ModelingMark Smales, Ph.D., Professor, Biotechnology, Biosciences, University of KentHere we described the application of an intact cell MALDI-ToF mass spectrometry fingerprinting method coupled with mathematical modeling to the cell line construction process for the prediction and isolation of high producing cell lines. We show how MALDI-ToF mass spectrometry data of cell lines gathered at the 96 deep well plate stage of cell line construction can be used to predict the phenotype of mammalian cell lines at the 10 L fermenter scale using a Partial Least Squares Discriminant Analysis (PLS-DA) model. The modeling approach provides the basis for the early prediction of cell line performance in cGMP manufacturing-scale bioreactors. We will discuss the possibility of extending the application to product quality attributes.



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SINGLE-USE, MONITORING QUALITY & PROCESS EXCELLENCE STRATEGIES

14:00 Chairperson’s RemarksRavinder Bhatia, MSc, Scientific Director, PDMS/API-LM, Janssen Research & Development

14:05 Case Study: Scale-Up of an Allogeneic Cell Therapy Product using Single-Use SystemsRavinder Bhatia, MSc, Scientific Director, PDMS/API-LM, Janssen Research & DevelopmentOne of the major challenges with cell therapy products is the development of a robust and scalable process to produce the product for clinical trials and commercialization. Currently, numerous technologies are available for the scale-up of an allogeneic cell therapy product in static (e.g. T-flasks and cell factories) or suspension (e.g. microcarriers, bioreactor type) cultures. In this presentation, a case study will be presented on process development and scale-up of an allogeneic human somatic cell therapy product using single-use technologies.

14:35 Combining Multi-Dimensional Fluorescence Spectroscopy and Chemometric Analysis for Quantitative Bioprocess MonitoringAlan G. Ryder, Ph.D., Senior Lecturer, Nanoscale Biophotonics Laboratory, School of Chemistry, National University of Ireland, GalwayMulti-dimensional fluorescence spectroscopy (MDFS) was used for quantitative predictive analysis of glycoprotein production and content in CHO cell fed-batch process. MDFS spectra of complex solutions were sensitive to compositional change and as cultivation progressed, amino acid, and glycoprotein product emission varied as the chemical composition changed and culture progress could be monitored quantitatively using a variety of multivariate analysis techniques. In one case, unique dityrosine emission from product glycoprotein could be used to follow product formation. The MDFS variance could also be used to generate quantitative predictive models of process performance based on glycoprotein yield.

15:05 Using Different QbD Tools to Support Scale-Down and Scale-Up of Bioprocesses: Examples from Small and Large MoleculesJose C. Menezes, Ph.D., Professor, Bioengineering and Biosciences, Technical University of LisbonThe use of disciplines from the QbD (Quality by Design) tool box will be demonstrated to support science-based bioprocess industrialization and manufacturing (e.g., design-spaces, multivariate end-point and batch trajectory control). Scale-up with PAT tools and/or validated scale-down models for DoE and troubleshooting will be highlighted for small and large molecules. Process performance and product quality will be considered in these approaches.

15:35 Monoliths as PAT Tools for Bioprocess ImprovementOliver Spadiut, Ph.D., Group Leader, Integrated Bioprocess Development, Biochemical Engineering, Vienna University of TechnologyMonolithic columns are a special type of chromatography column which can be used for the purification of different biomolecules. They have become popular due to their high mass transfer properties and short purification times. However, they also describe powerful PAT tools for bioprocess monitoring and development. I will show how monoliths can be used as efficient impurity monitoring tools during bioreactor cultivations but also across unit operations for recombinant protein production processes with yeast.

16:05 Hybrid Modeling as a QbD Tool for PAT in BiopharmaMoritz von Stosch, Ph.D., Lecturer, Chemical Engineering and Advanced Materials, Science, Agriculture and Engineering, Newcastle University; CEO, HybPAT TechnologiesProcess understanding is at the heart of the PAT initiative and QbD paradigm. The integration of Risk Analysis, Design of Experiments and Multivariate Data Analysis (MVDA) is the predominantly applied approach in biopharma to understand processes, nowadays. In this talk, it will be shown that the integration of fundamental process knowledge along with MVDA into hybrid models has the potential to improve the prediction performance, reduce the experimental effort and support the knowledge exchange between scales.



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HOTEL & TRAVEL INFORMATION Conference Venue and Hotel: EPIC SANA Lisboa Hotel

Avenida Engenheiro Duarte Pacheco 15,

1070-100 Lisbon, Portugal

Phone: +351-211-597-300

Reservations: Go to the travel page of PEGSummitEurope.com

Discounted Room Rate: €150 single/ €170 double ** includes complimentary breakfast & internet

Discounted Room Cut-off Date: 13 October 2015

For additional information go to the travel page of PEGSummitEurope.com


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SPONSORSHIP, EXHIBIT, AND LEAD GENERATION OPPORTUNITIESCHI offers comprehensive sponsorship packages which include presentation opportunities, exhibit space, branding and networking with specific prospects. Sponsorship allows you to achieve your objectives before, during, and long after the event. Any sponsorship can be customized to meet your company’s needs and budget. Signing on early will allow you to maximize exposure to qualified decision-makers.

Presentations – Available Within the Main Agenda!Showcase your solutions to a guaranteed, targeted audience. Package includes a 15 or 30-minute podium presentation on the scientific agenda, exhibit space, branding, full conference registrations, use of the event mailing list and more.

Luncheon PresentationsOpportunity includes a 30-minute podium presentation in the main session room. Lunch will be served to all delegates in attendance. A limited number of presentations are available for sponsorship and they will sell out quickly. Sign on early to secure your talk!

Invitation-Only VIP Dinner/Hospitality SuiteSponsors will select their top prospects from the conference pre-registration list for an evening of networking at the hotel or at a choice local venue. CHI will extend invitations, conduct follow-up and confirm attendees. The evening will be customized to meet with your specific objectives.

Additional branding and promotional opportunities are available, including:• Conference Tote Bags• Literature Distribution (Tote Bag Insert or Chair Drop)

• Badge Lanyards• Program Guide Advertisement...and more

Looking for additional ways to drive leads to your sales team? CHI’s Lead Generation Programs will help you obtain more targeted, quality leads throughout the year utilizing CHI’s database of over 800,000. A minimum of 100 leads with full contact information is guaranteed per program. Opportunities include:• Whitepapers • Web Symposia

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For more information, please contact:

Companies A-KJason GerardiBusiness Development Manager781-972-5452 | [email protected]

Companies L-Z Carol DinersteinDirector, Business Development781-972-5471 | [email protected]

CURRENT SPONSORS AND EXHIBITORSAs of June 4, 2015

AbCheck

Ajinomoto

Avacta Life Sciences

Berthold Technologies GmbH & Co

BIOVIA

CALIXAR

Chemical Computing Group Inc.

Cisbio Bioassays

Constant Systems Inc.

Fujifilm Diosynth Biotechnologies

Genedata AG

HORIBA Instruments Inc.

IBIS Technologies

IntelliCyt Corporation

Isogenica Ltd.

Malvern Instruments Inc.

MaxCyte, Inc.

Novozymes

Pall ForteBio

PhyNexus, Inc.

ProteoGenix

Randox Biosciences

Reichert Technologies

Schrödinger

SensiQ Technologies Inc.

TSI GmbH

TTP Labtech

Unchained Labs

Vaccinex Inc

Wacker Biotech GmbH

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ADDITIONAL REGISTRATION DETAILSEach registration includes all conference sessions, posters and exhibits, food functions, and access to the conference proceedings link.Handicapped Equal Access: In accordance with the ADA, Cambridge Healthtech Institute is pleased to arrange special accommodations for attendees with special needs. All requests for such assistance must be submitted in writing to CHI at least 30 days prior to the start of the meeting.To view our Substitutions/Cancellations Policy, go to www.healthtech.com/regdetailsVideo and or audio recording of any kind is prohibited onsite at all CHI events.

SHORT COURSES Commercial Academic, Government, Student* Hospital-affiliated

One short course €625 €375 €125

Two short courses €895 €625 €195

Monday, 2 November (Morning Short Courses) Thursday, 5 November (Dinner Short Courses)

SC1: Engineering of Bispecific Antibodies SC6: Troubleshooting and Engineering of Antibody Constructs

SC2: Mutation and Selection Strategies for Multi-Parameter Antibody Optimisation

SC7: Immunotherapy in the 21st Century: More Specificity, More Potency, Better Targeting

SC3: CHO Cell Engineering SC8: The Challenge of Protein Aggregation and Formation of Sub Visible Particles in the Development of Biopharmaceuticals

SC4: Protein Purification Strategies: Dealing with Proteins that Are Prone to Aggregate


CONFERENCE PRICING

PREMIUM PACKAGE - Best Value (Includes access to all conferences Monday-Friday, excludes short courses)

Registrations after 9 October, and on-site €2999 €1599 €695

STANDARD PACKAGE (Includes access to two conferences, excludes short courses)


BASIC PACKAGE (Includes access to one conference, excludes short courses)


Mon-Tues, 2-3 November Wed-Thurs am, 4-5 November Thurs pm - Fri, 5-6 November

Antibody Engineering Stream 1A: Display of Antibodies 1B: Bispecifics and Novel Products 1C: Cancer Biotherapeutics

Biologics Development Stream 2A: Optimisation & Development 2B: Aggregates & Particles 2C: Characterising Biotherapeutics

Impurities & Stability Stream 3A: Purification Technologies 3B: Aggregates & Particles 3C: Formulation & Stability

Bioproduction Stream 4A: Purification Technologies 4B: Bioreactor Design & Engineering 4C: Bioproduction: Scaling-Up & Down

Protein Expression Stream 5A: Engineering Expression Systems 5B: Applying Expression Platforms 5C: Bioproduction: Scaling-Up & Down

How to Register: [email protected] • P: 781.972.5400 or Toll-free in the U.S. 888.999.6288

Please use keycode PGE F when registering

CONFERENCE DISCOUNTS

Poster Submission - Discount (€45 Off): Poster abstracts are due by 2 October 2015. Once your registration has been fully processed, we will send an email containing a unique link allowing you to submit your poster abstract. If you do not receive your link within 5 business days, please contact [email protected]. *CHI reserves the right to publish your poster title and abstract in various marketing materials and products.

REGISTER 3 - 4th IS FREE: Individuals must register for the same conference or conference combination and submit completed registration form together for discount to apply.

Alumni Discount: CHI appreciates your past participation at PEGS. As a result of the great loyalty you have shown us, we are pleased to extend to you the exclusive opportunity to save an additional 20% off the registration rate.

Group Discounts: Special rates are available for multiple attendees from the same organization. For more in-formation on group discounts contact David Cunningham at 781-972-5472

* Alumni, Group, Protein Society or Antibody Society Membership, Twit-ter, LinkedIn, Facebook or any other promotional discounts cannot be combined. Discounts not applicable on Event Short Courses.


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SHORT COURSES












Scaling-Up & Down



Scaling-Up & Down



REGISTRATION INFORMATIONIf you are unable to attend but would like to purchase the PEGS Europe CD for €600 (plus shipping), please visit PEGSummitEurope.com. Massachusetts delivery will include sales tax.

http://www.healthtech.com/regdetails


mailto:reg%40healthtech.com?subject=


pegs final agenda pegs - pegs summit europe · of protein therapeutics, together with case studies...

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